heterocyclic macrocyclic ether chemotherapeutic agents

Abstract

Heterocyclic aromatic macrocyclic ether compounds, pharmaceutically acceptable salts of said compounds, and pharmaceutical compositions thereof are disclosed. Methods for treating or preventing cancer using said heterocyclic aromatic macrocyclic ether compounds, pharmaceutically acceptable salts of said compounds, and pharmaceutical compositions thereof are also disclosed.

Description

[0001] Related applications

[0002] This application claims priority to PCT patent application number PCT / CN2020 / 088589, filed May 5, 2020; and U.S. Provisional Patent Application No. 63 / 125,747, filed December 15, 2020; and U.S. Provisional Patent Application No. 63 / 060,331, filed August 3, 2020; all of which are incorporated herein by reference in their entirety. Background Technology

[0003] Receptor tyrosine kinases (RTKs) are cell surface enzymes that receive external signals, such as whether to grow and divide, and transmit these signals within the cell through kinase activity. Many RTKs are proto-oncogenes; abnormal RTK activity can drive cell survival, growth, and proliferation, leading to cancer and related diseases. This abnormal kinase activity can be caused by mutations, such as activating mutations in the kinase domain, gene rearrangements leading to fusion proteins containing intact kinase domains, amplification, and other mechanisms. RTK proto-oncogenes include ROS1, anaplastic lymphoma kinase (ALK), NTRK1 (encoding TRKA), NTRK2 (encoding TRKB), and NTRK3 (encoding TRKC).

[0004] ROS1 is an RTK proto-oncogene, and ROS1 rearrangements have been detected in non-small cell lung cancer (NSCLC), glioblastoma, inflammatory myofibroblastic tumor (IMT), cholangiocarcinoma, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, and spitzoid melanoma. Oncogenic ROS1 gene fusions contain fusions of the kinase domain of ROS1 (3' region) with the 5' region of various partner genes. Examples of ROS1 fusion-coupled genes observed in NSCLC include SLC34A2, CD74, TPM3, SDC4, EZR, LRIG3, KDELR2, CEP72, CLTL, CTNND2, GOPC, GPRC6A, LIMA1, LRIG3, MSN, MYO5C, OPRM1, SLC6A17 (presumed), SLMAP, SRSF6, TFG, TMEM106B, TPD52L1, ZCCHC8, and CCDC6. Other fusion partners include CAPRIN1, CEP85L, CHCHD3, CLIP1 (presumed), EEF1G, KIF21A (presumed), KLC1, SART3, ST13 (presumed), TRIM24 (presumed), ERC1, FIP1L1, HLAA, KIAA1598, MYO5A, PPFIBP1, PWWP2A, FN1, YWHAE, CCDC30, NCOR2, NFKB2, APOB, PLG, RBP4, and GOLGB1.

[0005] ALK is an RTK proto-oncogene, and ALK rearrangements have been detected in many cancers, including NSCLC, anaplastic large cell lymphoma (ALCL), IMT, diffuse large B-cell lymphoma (DLBCL), esophageal squamous cell carcinoma (ESCC), renal medullary carcinoma, renal cell carcinoma, breast cancer, colon cancer, serous ovarian cancer, papillary thyroid carcinoma, and Spitz nevus-like tumor, as well as ALK activating mutations detected in neuroblastoma. Oncogenic ALK gene fusions contain fusions of the kinase domain (3' region) of ALK with the 5' region of more than 20 different partner genes, the most common of which are EML4 in NSCLC and NPM in ALCL. Other partner somatic genes include TMP1, WDCP, GTF2IRD1, TPM3, TPM4, CLTC, LMNA, PRKAR1A, RANBP2, TFG, FN1, KLC1, VCL, STRN, HIP1, DCTN1, SQSTM1, TPR, CRIM1, PTPN3, FBXO36, ATIC, and KIF5B.

[0006] NTRK1, NTRK2, and NTRK3 are RTK proto-oncogenes encoding TRK family kinases. Chromosomal rearrangements of NTRK1, NTRK2, and NTRK3 are detected at low frequencies in many cancers. However, for the treatment of ROS1-positive or ALK-positive patients, TRK inhibition (particularly in the central nervous system (CNS)) is associated with adverse reactions, including dizziness / ataxia / gait disturbances, paresthesia, weight gain, and cognitive changes.

[0007] Existing drugs for treating oncogenic ROS1 and ALK have substantial deficiencies. These deficiencies may manifest as one or more of the following: associated TRK inhibition, limited CNS activity, and insufficient activity against resistance mutations. Treatment of ROS1-positive or ALK-positive patients with concomitant TRK inhibition is associated with adverse reactions, particularly in the CNS, including dizziness / ataxia / gait disturbances, paresthesia, weight gain, and cognitive changes. In addition, there is a need for CNS penetrants and TRK-saving inhibitors of ROS1 with wild-type ROS1 kinase domains and acquired resistance mutations, which may occur alone or in combination, including G2032R, D2033N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, L2032K, and L2086F. Similarly, there is a need for CNS penetrants and TRK-saving inhibitors of ALK with acquired resistance mutations. A variety of ALK resistance mutations, occurring alone or in combination, have been reported, including G1202R, L1196M, G1269A, C1156Y, I1171T, I1171N, I1171S, F1174L, V1180L, S1206Y, E1210K, 1151Tins, F1174C, G1202del, D1203N, S1206Y, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, and F1245V. Summary of the Invention

[0008] One aspect disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0009]

[0010] in

[0011] Q is CH or N;

[0012] Z is either CR5 or N;

[0013] X is a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen; wherein the 5-membered heteroaryl group is substituted by R2 appearing 0, 1 or 2 times.

[0014] Y is a heteroaryl group selected from the group consisting of: 2,3-substituted furanyl, 2,3-substituted furanyl, 3,4-substituted furanyl, 1,2-substituted imidazolyl, 1,5-substituted imidazolyl, 1,5-substituted imidazolyl, 4,5-substituted 1,2,3-oxadiazolyl, 3,4-substituted 1,2-oxadiazolyl, 4,5 ... -substituted 1,2-imoxazolyl, 4,5*-substituted 1,3-imoxazolyl, 1*,2-substituted phenylene, 1,5*-substituted pyrazolyl, 4*,5-substituted pyrazolyl, 3,4*-substituted pyridazinyl, 4*,5-substituted pyridazinyl, 2,3*-substituted pyridinyl, 3*,4-substituted pyridinyl, 3,4*-substituted pyridinyl, 4,5*-substituted pyrimidinyl, 1*,2-substituted 1,2*-substituted pyrrolidone, 2,3*-substituted pyrrolidone, 3*,4-substituted pyrrolidone, 4,5*-substituted 1,2,3-thiazolyl, 3,4*-substituted 1,2-thiazolyl, 4*,5-substituted 1,2-thiazolyl, 4,5*-substituted 1,2,3-thiazolyl, 3,4*-substituted 1,2-thiazolyl, 4*,5-substituted 1,2-thiazolyl 4,5*-substituted 1,2-imidazolyl, 4,5*-substituted 1,3-imidazolyl, 2*,3-substituted imidaphenyl, 2,3*-substituted imidaphenyl, 3*,4-substituted imidaphenyl, 4,5*-substituted 1,2,3-triazinyl, 1,5*-substituted 1,2,3-triazolyl and 3,4*-substituted 1,2,4-triazolyl; wherein the heteroaryl group is substituted by R3 0, 1 or 2 times;

[0015] * indicates the connection point between X or Y and the methylene group bonded to X and Y;

[0016] In Y, the heteroaryl ring atoms at the α-position of the connection point with the methylene group and the β-position of the connection point with the aromatic ring containing Z are carbon, oxygen, or sulfur.

[0017] R1 is selected from the group consisting of H, methyl, and hydroxymethyl;

[0018] Each instance of R2 is independently selected from the following group: CN, halogen, C 1-4 Alkoxy, C 1-4Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 cycloalkyl and C 3-6 Heterocyclic groups;

[0019] Each instance of R3 is independently selected from the following group: H, halogen, CN, C. 1-4 Alkoxy, halogenated -C 1-4 Alkyl and C 1-4 Alkyl; and

[0020] R4 and R5 are each independently H or F;

[0021] The condition is that the compound is not

[0022] In some embodiments, this disclosure provides a pharmaceutical composition suitable for treating or preventing cancer in a subject, comprising an effective amount of any compound described herein (e.g., compounds of this disclosure, such as compounds of formula (I) or pharmaceutically acceptable salts thereof) and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical formulation may be used to treat or prevent the ailment or disease described herein.

[0023] One aspect of this disclosure is a method of treating cancer characterized by one or more mutations in the ROS1 or ALK genes, comprising administering to a subject in need an effective amount of a compound disclosed herein (e.g., a compound of formula (I) or any embodiment thereof disclosed herein). In some embodiments, the compound is an inhibitor of ROS1; in other embodiments, the compound is an inhibitor of ALK; and in still other embodiments, the compound is an inhibitor of both ROS1 and ALK. In some aspects, the human subject requires this treatment.

[0024] These cancers include, but are not limited to, non-small cell lung cancer, inflammatory myofibroblastic tumor, ovarian cancer, Spitz nevus-like melanoma, glioblastoma, cholangiocarcinoma, gastric cancer, colorectal cancer, angiosarcoma, anaplastic large cell lymphoma, diffuse large B-cell lymphoma, esophageal squamous cell carcinoma, renal medullary carcinoma, renal cell carcinoma, breast cancer, papillary thyroid carcinoma, and neuroblastoma.

[0025] In some implementations, methods of treating or preventing cancer may include the combined administration of a compound of formula (I) and one or more other chemotherapeutic agents. Detailed Implementation

[0026] definition

[0027] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art. The following references provide those skilled in the art with general definitions of many terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd edition, 1994); The Cambridge Dictionary of Science and Technology (Walker, ed., 1988); The Glossary of Genetics, 5th edition, R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). Unless otherwise stated, as used herein, the following terms have the meanings assigned to them as follows.

[0028] In some implementations, chemical structures with corresponding chemical names are disclosed. In case of conflict, the meaning of the chemical structure shall prevail, rather than the name.

[0029] In this disclosure, terms such as “comprises,” “comprising,” “containing,” and “having” may have the meanings given to them by U.S. Patent Law and may mean “includes,” “including,” etc.; “consisting essentially of” or “consists essentially” also have the meanings given to them by U.S. Patent Law, and the terms are open-ended, allowing for more than what is listed, as long as the basic or novel features of the listed content are not substantially altered by the presence of more than what is listed, but excluding prior art embodiments.

[0030] Unless specifically stated or obvious from the context, the term “or” as used herein shall be understood as inclusive. Unless specifically stated or obvious from the context, the terms “a / an” and “the” as used herein shall be understood as singular or plural.

[0031] The term "acyl" is recognized in the art and refers to a group represented by the general formula hydrocarbon C(O)-, preferably an alkyl C(O)-.

[0032] The term "acylamino" is recognized in the art and refers to an amino group that has been substituted with an acyl group, and can be represented by, for example, a hydrocarbon group C(O)NH-.

[0033] The term "acyloxy group" is recognized in the art and refers to a group represented by the general formula hydrocarbon group C(O)O-, preferably a group represented by alkyl group C(O)O-.

[0034] The term "alkoxy" refers to an alkyl group linked to an oxygen atom, preferably a lower alkyl group. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc.

[0035] The term "alkoxyalkyl" refers to an alkyl group that has been substituted with an alkoxy group, and can be represented by the general formula alkyl-O-alkyl.

[0036] As used herein, the term "alkenyl" refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyl" and "substituted alkenyl," the latter referring to an alkenyl moiety having substituents on one or more carbons of the alkenyl group. Such substituents may be present on one or more carbons, which may or may not be contained in one or more double bonds. Furthermore, unless stability is limited, these substituents include all substituents considered for alkyl groups, as described below. For example, substitution of the alkenyl group with one or more alkyl, carbocyclic, aryl, heterocyclic, or heteroaryl groups is considered.

[0037] "Alkyl" or "alkane" refers to a fully saturated straight-chain or branched non-aromatic hydrocarbon. Generally, unless otherwise defined, straight-chain or branched alkyl groups have 1 to about 20 carbon atoms, preferably 1 to about 10 carbon atoms. Examples of straight-chain and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl. C1-C6 straight-chain or branched alkyl groups are also called "lower alkyl groups".

[0038] Furthermore, as used throughout the specification, examples, and claims, the term "alkyl" (or "lower alkyl") is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter referring to an alkyl moiety having a substituent having hydrogen substituted on one or more carbons of the hydrocarbon backbone. Unless otherwise specified, such substituents may include, for example, halogens, hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (e.g., thioesters, thioacetates, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphate groups, phosphonates, hypophosphonates, amino groups, amide groups, amidine groups, imine groups, cyano groups, nitro groups, azide groups, mercapto groups, alkylthio groups, sulfate groups, sulfonates, aminosulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, aralkyl groups, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that, where appropriate, the substituted portion of the hydrocarbon chain may itself be substituted. For example, the substituents of the substituted alkyl group may include substituted and unsubstituted forms of amino, azide, imino, amide, phosphoryl (including phosphonates and hypophosphonates), sulfonyl (including sulfates, sulfonamides, aminosulfonyls, and sulfonates), and silyl, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylic esters, and esters), -CF3, -CN, etc. Exemplary substituted alkyl groups are described below. Cycloalkyl groups may be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl groups, -CF3, -CN, etc.

[0039] Term "C" x-y "When used in conjunction with chemical motifs such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, it means to include groups containing x to y carbons in the chain. For example, the term 'C'..." x-y "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched alkyl groups containing x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. C0 alkyl indicates hydrogen, where the group is located at the terminal position, or, if internal, is a bond. The term "C"... 2-y "Alkenyl" and "C" 2-y "Alkyne" refers to a substituted or unsubstituted unsaturated aliphatic group whose length and possible substitutions are similar to those of the alkyl groups described above, but which contain at least one double or triple bond.

[0040] As used herein, the term "alkylamino" refers to an amino group that is substituted with at least one alkyl group.

[0041] As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group and can be represented by the general formula alkylS-.

[0042] As used herein, the term "alkynyl" refers to an aliphatic group containing at least one triple bond, and is intended to include both "unsubstituted alkynyl" and "substituted alkynyl," the latter referring to an alkynyl moiety having substituents replacing one or more carbons of the alkynyl group. Such substituents may be present on one or more carbons, which may or may not be included in one or more triple bonds. Furthermore, unless stability is limited, such substituents include all substituents contemplated for alkyl groups as discussed above. For example, it is contemplated that the alkynyl group be substituted with one or more alkyl, carbocyclic, aryl, heterocyclic, or heteroaryl groups.

[0043] As used herein, the term "amide" refers to a group,

[0044]

[0045] Each R 30 Independently representing a hydrogen or hydrocarbon group, or two Rs 30 Together with the N atoms they are attached to, they form heterocycles with 4 to 8 atoms in the ring structure.

[0046] The terms "amine" and "amino" are recognized in the art and refer to unsubstituted and substituted amines and their salts, such as portions that can be represented by the following formula.

[0047]

[0048] Each R 31 Independently representing a hydrogen or hydrocarbon group, or two Rs 31 Together with the N atoms they are attached to, they form heterocycles with 4 to 8 atoms in the ring structure. As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0049] As used herein, the term "aralkyl" refers to an alkyl group that has been substituted with an aryl group.

[0050] As used herein, the term "aryl" includes a substituted or unsubstituted monocyclic aromatic group, wherein each ring atom is a carbon atom. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is aromatic, for example, the other rings may be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc.

[0051] The term "carbamate" is recognized in the art and refers to a group.

[0052]

[0053] Where R 32 and R33 Independently representing hydrogen or a hydrocarbon group, such as alkyl, or R 32 and R 33 Together with the inserted atoms, they form heterocycles with 4 to 8 atoms in the ring structure.

[0054] As used herein, the terms "carbocycle" and "carbocyclic" refer to saturated or unsaturated rings in which each ring atom is carbon. The term carbocyclic includes aromatic and non-aromatic carbocyclic rings. Non-aromatic carbocyclic rings include cycloalkane rings and cycloalkene rings; all carbon atoms in cycloalkane rings are saturated, and cycloalkene rings contain at least one double bond.

[0055] The term "carbocyclic ring" includes 5-7 membered monocyclic rings and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocyclic ring can be selected from saturated rings, unsaturated rings, and aromatic rings. Carbocyclic rings include bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused carbocyclic ring" refers to a bicyclic carbocyclic ring in which each ring shares two adjacent atoms with the other ring. Each ring of a fused carbocyclic ring can be selected from saturated rings, unsaturated rings, and aromatic rings. In an exemplary embodiment, an aromatic ring (e.g., phenyl) may be fused with a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated bicyclic, unsaturated bicyclic, and aromatic bicyclic rings is included in the definition of a carbocyclic ring, provided that the valence allows. Exemplary "carbocyclic rings" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocyclic rings include decahydronaphthalene, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. The “carbocyclic ring” may be substituted at any one or more positions capable of carrying hydrogen atoms.

[0056] "Cycloalkyl" refers to a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic compounds. Generally, unless otherwise defined, monocyclic cycloalkyl compounds have 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms. The second ring of a bicyclic cycloalkyl compound can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyl compounds include bicyclic molecules in which one, two, or three or more atoms are shared between two rings. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl compound in which each ring shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl compound can be selected from saturated, unsaturated, and aromatic rings. "Cycloalkenyl" refers to a cyclic hydrocarbon containing one or more double bonds.

[0057] As used herein, the term "carbocyclic alkyl" refers to an alkyl group that has been substituted with a carbocyclic group.

[0058] As used in this article, the term "C" 3-4"Cycloalkylmethyl" refers to a methyl group that has been substituted by a carbocyclic group containing 3 to 4 carbon atoms.

[0059] The term "carbonate" is generally accepted in the art and refers to the group -OCO2-R. 34 , where R 34 It represents a hydrocarbon group.

[0060] As used herein, the term "carboxyl" refers to a group represented by the formula -CO2H.

[0061] As used herein, the term "ester" refers to the group -C(O)OR 35 , where R 35 It represents a hydrocarbon group.

[0062] As used herein, the term "ether" refers to a hydrocarbon group that is attached to another hydrocarbon group via oxygen. Therefore, the ether substituent of a hydrocarbon group can be alkyl-O-. Ethers can be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocyclic-O-heterocycles and aryl-O-heterocycles. Ethers include "alkoxyalkyl" groups, which can be represented by the general formula alkyl-O-alkyl.

[0063] As used herein, the terms “halogen” and “halogen” refer to halogens and include chlorine, fluorine, bromine and iodine groups.

[0064] As used herein, the terms “heteroaryl alkyl” and “heteroaryl alkyl” refer to alkyl groups substituted with heteroaryl groups.

[0065] As used herein, the term "heteroalkyl" refers to a saturated or unsaturated chain of a carbon atom and at least one heteroatom, wherein the two heteroatoms are not adjacent.

[0066] The terms "heteroaryl" and "hetaryl" encompass substituted or unsubstituted aromatic monocyclic structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structure contains at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic systems having two or more rings, wherein two or more carbons are common to two adjacent rings, and wherein at least one ring is heteroaromatic; for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic groups. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0067] In compounds of formula (I), the asterisk (*) symbol on the heteroaryl ring moiety corresponding to X or Y indicates the ring atom of the part bonded to the methylene group between X and Y, as illustrated below:

[0068]

[0069] For example, "1*,5-substituted imidazolyl" in Y means substituted:

[0070]

[0071] As shown above, the IUPAC numbering rules for heteroaryl rings are used throughout the specification to specify the positions of ring atoms. In this example, the imidazolyl group at position 1 is bonded to the methylene group and is therefore indicated by an asterisk. The asterisk symbol is used in the names and structures of the heteroaryl groups X and Y. Here, for Y, the ring atom at position 5 is not marked because it is bonded to the phenyl group carrying the variable R4.

[0072] For X, an exemplary ring would be “1,5*-substituted imidazolyl” as shown below.

[0073]

[0074] In the names and structures of cyclo-X heteroaryl groups, the ring atoms bonded to the methylene group (position 5 in this example) are indicated by an asterisk. The ring atoms bonded to the aromatic ring carrying the Q group are not labeled.

[0075] As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0076] The terms "heterocyclyl," "heterocycle," and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structure contains at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic systems having two or more rings, wherein two or more carbons are common to two adjacent rings, and wherein at least one ring is heterocyclic; for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic groups. Heterocyclic groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, etc.

[0077] As used herein, the term "heterocyclic alkyl" refers to an alkyl group that has been substituted with a heterocyclic group.

[0078] As used herein, the term "hydrocarbon group" refers to a group bonded by carbon atoms, which does not have =O or =S substituents and typically has at least one carbon-hydrogen bond and a predominant carbon skeleton, but may optionally contain heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbon groups for the purposes of this application, but substituents such as acetyl (which has a =O substituent on the linking carbon) and ethoxy (which is linked by oxygen rather than carbon) are not hydrocarbon groups. Hydrocarbon groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, ynyl, and combinations thereof.

[0079] As used herein, the term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group.

[0080] When used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, the term "lower" means including groups in which there are ten or fewer, preferably six or fewer, non-hydrogen atoms in the substituents. For example, "lower alkyl" refers to an alkyl group containing ten or fewer carbon atoms, preferably six or fewer. In some embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents as defined herein are referred to as lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, for example, when hydroxyalkyl and aralkyl are described (in which case, for example, when calculating the carbon atoms in the alkyl substituents, the atoms in the aryl group are not counted).

[0081] The terms "polycyclic," "polycycle," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic) in which two or more atoms are shared by two adjacent rings; for example, the ring is a "fused ring." Each ring of the polycyclic ring can be substituted or unsubstituted. In some embodiments, each ring of the polycyclic ring contains 3 to 10 atoms, preferably 5 to 7.

[0082] The term "silyl group" refers to a silicon moiety that has three hydrocarbon groups attached to it.

[0083] The term "substituted" refers to a portion having a substituent having hydrogen substituted on one or more carbons of the skeleton. It should be understood that "substituted" or "substituted" includes the implicit limiting condition that such substitution meets the permissible valence of the substituted atom and the substituent, and that said substitution produces a stable compound, for example, which does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For suitable organic compounds, permissible substituents can be one or more and can be the same or different. For purposes of disclosure, heteroatoms (such as nitrogen) can have hydrogen substituents and / or any permissible substituent of the organic compounds described herein that meets the heteroatom valence. Substituents may include any substituents described herein, such as halogens, hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (e.g., thioesters, thioacetic acids, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphate groups, phosphonates, hypophosphonates, amino groups, amide groups, amidine groups, imine groups, cyano groups, nitro groups, azide groups, mercapto groups, alkylthio groups, sulfate groups, sulfonates, aminosulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, aralkyl groups, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that the substituents themselves may be substituted where appropriate. Unless specifically stated as “unsubstituted,” references to the chemical portion herein should be understood to include substituted variants. For example, references to an “aryl” group or portion implicitly include both substituted and unsubstituted variants.

[0084] The term "sulfate" is recognized in the art and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0085] The term "sulfonamide" is recognized in the art and refers to a group represented by the following general formula.

[0086]

[0087] Where R 36 and R 37 Independently representing hydrogen or a hydrocarbon group, such as alkyl, or R 36 and R 37 Together with the inserted atoms, they form heterocycles with 4 to 8 atoms in the ring structure.

[0088] The term "sulfoxide" is generally accepted in the art and refers to the group -S(O)-R. 38 , where R 38 It represents a hydrocarbon group.

[0089] The term "sulfonate" is recognized in the art and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0090] The term "sulfone" is generally accepted in the art and refers to the group -S(O)2-R. 39 , where R 39 It represents a hydrocarbon group.

[0091] As used herein, the term "thioalkyl" refers to an alkyl group that has been substituted with a thiol group.

[0092] As used herein, the term "thioester" refers to the group -C(O)SR. 40 or -SC(O)R 40 , where R 10 It represents a hydrocarbon group.

[0093] As used in this article, the term "thioether" is equivalent to an ether in which oxygen is replaced by sulfur.

[0094] The term "urea" is recognized in the art and can be represented by the following general formula.

[0095]

[0096] Where R 41 and R 42 Independently representing hydrogen or a hydrocarbon group, such as alkyl, or R 41 The emergence of R 42 Together with the inserted atoms, they form heterocycles with 4 to 8 atoms in the ring structure.

[0097] The term "protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce, or prevent the reactivity of that functional group. Typically, protecting groups can be selectively removed during synthesis as needed. Examples of protecting groups can be found in Greene and Wuts, *Protective Groups in Organic Chemistry*, 3rd ed., 1999, John Wiley & Sons, NY, and Harrison et al., *Compendium of Synthetic Organic Methods*, vols. 1–8, 1971–1996, John Wiley & Sons, NY. Representative nitrogen-protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), triphenylmethyl and substituted triphenylmethyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl (“FMOC”), nitro-veratroloxycarbonyl (“NVOC”), etc. Representative hydroxyl-protecting groups include, but are not limited to, those groups in which the hydroxyl group is acylated (esterified) or alkylated, such as benzyl and triphenylmethyl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.

[0098] In some embodiments, the compounds of this disclosure may be racemic. In some embodiments, the compounds of this disclosure may be enriched with one enantiomer. For example, the compounds of this disclosure may have greater than about 30% ee, about 40% ee, about 50% ee, about 60% ee, about 70% ee, about 80% ee, about 90% ee, or even about 95% or greater ee. In some embodiments, the compounds of this disclosure may have more than one stereocenter. In some such embodiments, the compounds of this disclosure may be enriched with one or more diastereomers. For example, the compounds of this disclosure may have greater than about 30% de, about 40% de, about 50% de, about 60% de, about 70% de, about 80% de, about 90% de, or even about 95% or greater de.

[0099] In some embodiments, the therapeutic agent may be enriched to primarily provide one enantiomer of the compound (e.g., compound of formula (I)). The enantiomer-rich mixture may contain, for example, at least about 60 mol% of one enantiomer, or more preferably at least about 75, about 90, about 95, or even about 99 mol%. In some embodiments, the compound rich in one enantiomer is substantially free of the other enantiomer, where substantially free means, for example, that the substance in question comprises less than about 10%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1% of the other enantiomer in the composition or compound mixture. For example, if the composition or compound mixture contains about 98 grams of the first enantiomer and about 2 grams of the second enantiomer, it can be said to contain about 98 mol% of the first enantiomer and only about 2% of the second enantiomer.

[0100] In some embodiments, the therapeutic agent may be enriched to primarily provide one diastereomer of the compound (e.g., compound of formula (I)). The diastereomer-rich mixture may contain, for example, at least about 60 mol% of one diastereomer, or more preferably at least about 75, about 90, about 95, or even about 99 mol%.

[0101] In some embodiments, a portion of the compound exists as a mixture of tautomers. A "tautomer" is a structural isomer of the portion or compound that readily interconverts with another structural isomer. For example, the pyrazole ring has two tautomers:

[0102]

[0103] They differ in the positions of the π bonds and hydrogen atoms. Unless otherwise explicitly stated, a diagram of one tautomer of a part or compound includes all possible tautomers.

[0104] The term "subject" intended for application includes, but is not limited to, humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quails, and / or turkeys. Humans are preferred subjects.

[0105] As used herein, a therapeutic agent that "prevents" a condition or disease refers to a compound that, in a statistically significant sample, reduces the occurrence of a condition or disease in a treated sample relative to an untreated control sample, or delays the onset of one or more symptoms of a condition or disease or reduces its severity relative to an untreated control sample. These effects are also referred to as "preventive" effects. Therefore, as used herein, unless otherwise stated, the terms "prevention" and "preventing" refer to methods for obtaining beneficial or desired outcomes, including but not limited to preventive benefits. For preventive purposes, a therapeutic agent may be administered to a patient at risk of developing a specific disease or to a patient reporting one or more physiological symptoms of a disease, even if the disease may not yet be diagnosed. In one embodiment, a therapeutic agent is administered prior to the clinical manifestation of an undesirable condition (e.g., a disease or other undesirable state of the subject) to obtain a preventive benefit (e.g., it protects the subject from developing the undesirable condition).

[0106] As used herein, unless otherwise stated, the term "treatment" means a therapeutic or palliative measure. Beneficial or desired clinical outcomes include, but are not limited to, overall or partial relief of symptoms associated with the disease or condition or disorder, reduction of disease severity, stabilization (i.e., non-worsening) of the disease state, delay or slowing of disease progression, improvement or relief of the disease state (e.g., one or more disease symptoms), and remission (whether partial or complete), whether detectable or undetectable. "Treatment" may also mean prolonged survival compared to expected survival without treatment. In one embodiment, "treatment" includes administering a therapeutic agent (i.e., designed to reduce, improve, or stabilize an existing undesirable condition or its side effects) after the onset of an undesirable disorder.

[0107] The term "prodrug" is intended to include compounds (e.g., compounds of formula (I)) that are convertible under physiological conditions to the therapeutically active agents of this disclosure. Common methods for preparing prodrugs involve hydrolyzing one or more selected moieties under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of a subject. For example, esters or carbonates (e.g., esters or carbonates of alcohols or formic acids) are preferred prodrugs of this disclosure. In some embodiments, some or all of the compounds of formula (I) in the formulations shown above may be replaced by a corresponding suitable prodrug, e.g., wherein the hydroxyl groups in the parent compound are present in the form of an ester or carbonate or formic acid.

[0108] As used herein, "effective amount" means an amount sufficient to achieve the desired biological effect. As used herein, "therapeutic effective amount" means an amount sufficient to achieve the desired therapeutic effect. For example, a therapeutic effective amount could be an amount sufficient to improve at least one sign or symptom of cancer.

[0109] A “response” to treatment can include a reduction or improvement of negative symptoms, a decrease in the progression of the disease or its symptoms, an increase in beneficial symptoms or clinical outcomes, a reduction in side effects, stabilization of the disease, partial or complete cure of the disease, and other responses.

[0110] As used herein, unless otherwise stated, the term “relapse” refers to a condition, disease, or disorder that has responded to prior treatment (e.g., achieved a complete response) and then progressed. Prior treatment may include one or more therapies.

[0111] As used herein, unless otherwise stated, the term "refractory" means a condition, disease, or ailment that does not respond to prior treatment, which may include one or more therapies.

[0112] compound

[0113] In one respect, this article provides a compound of formula (I) or an enantiomer thereof, a mixture of enantiomers or a tautomer thereof or a pharmaceutically acceptable salt thereof:

[0114]

[0115] in

[0116] Q is CH or N;

[0117] Z is either CR5 or N;

[0118] x is a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the 5-membered heteroaryl group is substituted by R2 appearing 0, 1 or 2 times.

[0119] Y is a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the 5- or 6-membered heteroaryl group is substituted by R3 appearing 0, 1 or 2 times.

[0120] In Y, the connection point of the methylene group bonded to X and Y and the connection point of the aromatic ring containing Z are on adjacent atoms, and the 5- or 6-membered heteroaryl ring atom at the α position of the connection point of the methylene group and the β position of the connection point of the aromatic ring containing Z is carbon, oxygen or sulfur.

[0121] R1 is selected from the group consisting of H, methyl, and hydroxymethyl;

[0122] Each instance of R2 is independently selected from the following group: H, CN, halogen, C. 1-4 Alkoxy, C 1-4 Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 cycloalkyl and C3-6 Heterocyclic groups;

[0123] Each instance of R3 is independently selected from the following group: H, halogen, CN, C. 1-4 Alkoxy, halogenated -C 1-4 Alkyl and C 1-4 Alkyl; and

[0124] R4 and R5 are each independently H or F;

[0125] The condition is that X is not a 3*,4-substituted pyrazolyl group, where * represents the connection point of X or Y with the methylene group bonded to X and Y.

[0126] In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is disclosed:

[0127]

[0128] in

[0129] Q is CH or N;

[0130] Z is either CR5 or N;

[0131] X is a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen; wherein the 5-membered heteroaryl group is substituted by R2 appearing 0, 1 or 2 times.

[0132] Y is a heteroaryl group selected from the group consisting of: 2,3-substituted furanyl, 2,3-substituted furanyl, 3,4-substituted furanyl, 1,2-substituted imidazolyl, 1,5-substituted imidazolyl, 1,5-substituted imidazolyl, 4,5-substituted 1,2,3-oxadiazolyl, 3,4-substituted 1,2-oxadiazolyl, 4,5-substituted... 1,2-Ixazolyl, 4,5*-substituted 1,2-Ixazolyl, 4,5*-substituted 1,3-Ixazolyl, 1*,2-substituted phenylene, 1,5*-substituted pyrazolyl, 4*,5-substituted pyrazolyl, 3,4*-substituted pyridazinyl, 4*,5-substituted pyridazinyl, 2,3*-substituted pyridinyl, 3*,4-substituted pyridinyl, 3,4*-substituted 4,5*-substituted pyridinyl, 1,2-substituted pyrrolyl, 1,2*-substituted pyrrolyl, 2,3*-substituted pyrrolyl, 3,4-substituted pyrrolyl, 4,5*-substituted 1,2,3-pyridiazolyl, 3,4*-substituted 1,2-pyridiazolyl, 4,5-substituted 1,2-pyridiazolyl, 4,5*-substituted 1,2-pyridiazolyl Thiazolyl, 4,5*-substituted 1,3-imidazolyl, 2*,3-substituted imidaphenyl, 2,3*-substituted imidaphenyl, 3*,4-substituted imidaphenyl, 4,5*-substituted 1,2,3-triazinyl, 1,5*-substituted 1,2,3-triazolyl and 3,4*-substituted 1,2,4-triazolyl; wherein the heteroaryl group is substituted by R3 0, 1 or 2 times;

[0133] * indicates the connection point between X or Y and the methylene group bonded to X and Y;

[0134] In Y, the heteroaryl ring atoms at the α-position of the connection point with the methylene group and the β-position of the connection point with the aromatic ring containing Z are carbon, oxygen, or sulfur.

[0135] R1 is selected from the group consisting of H, methyl, and hydroxymethyl;

[0136] Each instance of R2 is independently selected from the following group: H, CN, halogen, C. 1-4 Alkoxy, C 1-4 Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 cycloalkyl and C 3-6 Heterocyclic groups;

[0137] Each instance of R3 is independently selected from the following group: H, halogen, CN, C. 1-4 Alkoxy, halogenated -C 1-4 Alkyl and C 1-4 Alkyl; and

[0138] R4 and R5 are each independently H or F;

[0139] The condition is that the compound is not

[0140] In some embodiments, X is a 5-membered heteroaryl group selected from the group consisting of pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, and triazolyl. In some embodiments, X is selected from the group consisting of pyrazolyl and triazolyl. In some embodiments, X is selected from the group consisting of: 4*,5-substituted pyrazolyl, 4,5*-substituted pyrazolyl, 1*,5-substituted pyrazolyl, 4*,5-substituted isoxazolyl, 3*,4-substituted isoxazolyl, 3*,4-substituted isothiazolyl, 4*,5-substituted isothiazolyl, 4*,5-substituted imidazolyl, 1*,5-substituted imidazolyl, 1*,5-substituted triazolyl, and 4*,5-substituted triazolyl.

[0141] In some embodiments, X is a 5-membered heteroaryl group selected from the group consisting of pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, and triazolyl. In some embodiments, X is selected from the group consisting of pyrazolyl and triazolyl. In some embodiments, X is selected from the group consisting of: 4*,5-substituted pyrazolyl, 4,5*-substituted pyrazolyl, 1*,5-substituted pyrazolyl, 4*,5-substituted isoxazolyl, 4,5*-substituted isoxazolyl, 3*,4-substituted isoxazolyl, 3*,4-substituted isothiazolyl, 4*,5-substituted isothiazolyl, 4,5*-substituted isothiazolyl, 4*,5-substituted imidazolyl, 1*,5-substituted imidazolyl, 1*,5-substituted triazolyl, and 4*,5-substituted triazolyl.

[0142] In some implementations, X is selected from the group consisting of:

[0143]

[0144] * indicates the junction site of X with the methylene group bonded to X and Y; and

[0145] R2 is independently selected from the following groups: H, CN, halogen, C. 1-4 Alkoxy, C 1-4 Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 cycloalkyl and C 3-6 Heterocyclic group.

[0146] In one embodiment, X is an imidazolyl group. In one embodiment, X is not a 3,4-substituted imidazolyl group. In one embodiment, X is not... In one implementation, X is not... In another embodiment, X is a 3,4-substituted pyrazolyl group. In another embodiment, X is a 4,5-substituted pyrazolyl group. In another embodiment, X is a 4,5-substituted pyrazolyl group. In another embodiment, X is a 1,5-substituted pyrazolyl group. In one embodiment, X is... In one implementation, X is... In one implementation, X is...

[0147] In one embodiment, X is isoxazolyl. In one embodiment, X is 4*,5-substituted isoxazolyl. In one embodiment, X is 4,5*-substituted isoxazolyl. In one embodiment, X is 3*,4-substituted isoxazolyl. In one embodiment, X is... In one implementation, X is...

[0148] In one embodiment, X is an isothiazolyl group. In one embodiment, X is a 3,4-substituted isothiazolyl group. In one embodiment, X is a 4,5-substituted isothiazolyl group. In one embodiment, X is a 4,5-substituted isothiazolyl group. In one embodiment, X is... In one implementation, X is...

[0149] In one embodiment, X is an imidazolyl group. In one embodiment, X is a 4*,5-substituted imidazolyl group. In one embodiment, X is a 1*,5-substituted imidazolyl group. In one embodiment, X is...

[0150] In one embodiment, X is a triazolyl group. In one embodiment, X is a 1*,5-substituted triazolyl group. In one embodiment, X is a 4*,5-substituted triazolyl group. In one embodiment, X is... In one implementation, X is...

[0151] In one implementation, X is replaced by R2 that occurs 0 times (i.e., all open positions on X are H). In one implementation, X is replaced by R2 that does not occur H once. In one implementation, X is replaced by R2 that does not occur H twice.

[0152] R2 is independently selected from the following groups: H, halogen, CN, C. 1-4 Alkoxy, C 1-4 Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 cycloalkyl and C 3-6 Heterocyclic alkyl. In one embodiment, R2 is not H. In one embodiment, R2 is C. 1-4 Alkyl group. In one embodiment, R2 is methyl. In one embodiment, R2 is ethyl. In one embodiment, R2 is isopropyl. In one embodiment, R2 is cyclopropyl. In one embodiment, R2 is cyclobutyl. In one embodiment, R2 is cyclopropylmethyl. In one embodiment, R2 is -CHF2. In one embodiment, R2 is -CH2CHF2. In one embodiment, R2 is a halogroup. In one embodiment, R2 is a fluorinated group. In one embodiment, R2 is a chlorogroup. In one embodiment, R2 is CN. In one embodiment, R2 is methoxy.

[0153] In some implementations, X is selected from the group consisting of:

[0154]

[0155] In some embodiments, Y is selected from the group consisting of: 4,5-substituted pyrazolyl, 1,5*-substituted pyrazolyl, 3,4*-substituted pyrazolyl, 1,2-substituted imidazolyl, 5,1-substituted imidazolyl, 4,5*-substituted 1,3-imidazolyl, 3,4*-substituted 1,2-imidazolyl, 4,5-substituted 1,2-imidazolyl, 3,4*-substituted 1,2-imidazolyl, 4,5-substituted 1,2-imidazolyl, 2,3*-substituted pyridinyl, 3,4-substituted pyridinyl, 4,3-substituted pyridinyl, 4,5*-substituted pyrimidinyl, 1,5*-substituted 1,2,3-triazolyl, and 3,4*-substituted 1,2,4-triazolyl.

[0156] In some implementations, Y is selected from the group consisting of:

[0157]

[0158]

[0159] * indicates the junction of Y with the methylene group bonded to X and Y; and

[0160] R3 is selected from the following groups: H, halogen, CN, C. 1-4 Alkoxy, halogenated -C1-4 Alkyl and C 1-4 alkyl.

[0161] In one embodiment, Y is a 5-membered heteroaryl group. In one embodiment, Y is a pyrazolyl group. In one embodiment, Y is a 1,5*-substituted pyrazolyl group. In one embodiment, Y is a 4*,5-substituted pyrazolyl group. In one embodiment, Y is a 3,4*-substituted pyrazolyl group. In one embodiment, Y is... In one implementation, Y is In one implementation, Y is In one implementation, Y is...

[0162] In one embodiment, Y is an imidazolyl group. In one embodiment, Y is a 1*,2-substituted imidazolyl group. In one embodiment, Y is a 5*,1-substituted imidazolyl group. In one embodiment, Y is... In one implementation, Y is In one implementation, Y is

[0163] In one embodiment, Y is 1,2-imidazolyl. In one embodiment, Y is 3,4*-substituted 1,2-imidazolyl. In one embodiment, Y is 4*,5-substituted 1,2-imidazolyl. In one embodiment, Y is... In one implementation, Y is

[0164] In one embodiment, Y is 1,3-imidazolyl. In one embodiment, Y is 4,5*-substituted 1,3-imidazolyl. In one embodiment, Y is...

[0165] In one embodiment, Y is 1,2-imoxazolyl. In one embodiment, Y is 3,4*-substituted 1,2-imoxazolyl. In one embodiment, Y is 4*,5-substituted 1,2-imoxazolyl. In one embodiment, Y is... In one implementation, Y is

[0166] In one embodiment, Y is a triazolyl group. In one embodiment, Y is a 1,5*-substituted 1,2,3-triazolyl group. In one embodiment, Y is a 3,4*-substituted 1,2,4-triazolyl group. In one embodiment, Y is... In one implementation, Y is

[0167] In one embodiment, Y is a 6-membered heteroaryl group. In one embodiment, Y is a pyridyl group. In one embodiment, Y is a 2,3*-substituted pyridyl group. In one embodiment, Y is a 3*,4-substituted pyridyl group. In one embodiment, Y is a 4*,3-substituted pyridyl group. In one embodiment, Y is... In one implementation, Y is In one implementation, Y is In one implementation, Y is In one implementation, Y is In one implementation, Y is In one implementation, Y is

[0168] In one embodiment, Y is a pyrimidinyl group. In one embodiment, Y is a 4,5*-substituted pyrimidinyl group. In one embodiment, Y is...

[0169] In one implementation, Y is replaced by R3 occurring 0 times (i.e., all open positions on Y are H). In one implementation, Y is replaced by R3 occurring 1 time (not H). In one implementation, Y is replaced by R3 occurring 2 times (not H).

[0170] In one implementation, R3 is selected from the group consisting of: H, halogen, CN, C. 1-4 Alkoxy, halogenated -C 1-4 Alkyl and C 1-4 Alkyl group. In one embodiment, R3 is not H. In one embodiment, R3 is C. 1-4 Alkyl group. In one embodiment, R3 is methyl. In one embodiment, R3 is ethyl. In one embodiment, R3 is halogroup. In one embodiment, R3 is fluorogroup. In one embodiment, R3 is chlorogroup. In one embodiment, R3 is CN.

[0171] In one embodiment, X is a pyrazolyl group as described herein (e.g., a 4,5-substituted pyrazolyl group as described herein), and Y is a pyrazolyl group as described herein. In another embodiment, Y is an imidazolyl group as described herein. In another embodiment, Y is a 1,2-thiazolyl group as described herein. In another embodiment, Y is a 1,3-thiazolyl group as described herein. In another embodiment, Y is a 1,2-oxazolyl group as described herein. In another embodiment, Y is a triazolyl group as described herein. In another embodiment, Y is a pyridinyl group as described herein. In another embodiment, Y is a pyrimidinyl group as described herein.

[0172] In one embodiment, X is an isoxazolyl group as described herein, and Y is a pyrazolyl group as described herein. In another embodiment, Y is an imidazolyl group as described herein. In another embodiment, Y is a 1,2-thiazolyl group as described herein. In another embodiment, Y is a 1,3-thiazolyl group as described herein. In another embodiment, Y is a 1,2-oxazolyl group as described herein. In another embodiment, Y is a triazolyl group as described herein. In another embodiment, Y is a pyridinyl group as described herein. In another embodiment, Y is a pyrimidinyl group as described herein.

[0173] In one embodiment, X is an isothiazolyl group as provided herein, and Y is a pyrazolyl group as provided herein. In another embodiment, Y is an imidazolyl group as provided herein. In another embodiment, Y is a 1,2-isothiazolyl group as provided herein. In another embodiment, Y is a 1,3-isothiazolyl group as provided herein. In another embodiment, Y is a 1,2-oxazolyl group as provided herein. In another embodiment, Y is a triazolyl group as provided herein. In another embodiment, Y is a pyridyl group as provided herein. In another embodiment, Y is a pyrimidinyl group as provided herein.

[0174] In one embodiment, X is an imidazolyl group as described herein, and Y is a pyrazolyl group as described herein. In another embodiment, Y is an imidazolyl group as described herein. In another embodiment, Y is a 1,2-thiazolyl group as described herein. In another embodiment, Y is a 1,3-thiazolyl group as described herein. In another embodiment, Y is a 1,2-oxazolyl group as described herein. In another embodiment, Y is a triazolyl group as described herein. In another embodiment, Y is a pyridyl group as described herein. In another embodiment, Y is a pyrimidinyl group as described herein.

[0175] In one embodiment, X is a triazolyl group as described herein, and Y is a pyrazolyl group as described herein. In another embodiment, Y is an imidazolyl group as described herein. In another embodiment, Y is a 1,2-thiazolyl group as described herein. In another embodiment, Y is a 1,3-thiazolyl group as described herein. In another embodiment, Y is a 1,2-oxazolyl group as described herein. In another embodiment, Y is a triazolyl group as described herein. In another embodiment, Y is a pyridyl group as described herein. In another embodiment, Y is a pyrimidinyl group as described herein.

[0176] In some implementations, Q is CH. In other implementations, Q is N.

[0177] In some implementations, Z is CR5. In a specific implementation, R5 is H. In a specific implementation, R5 is F. In other implementations, Z is N.

[0178] In some implementations, R4 is H. In other implementations, R4 is F.

[0179] In some embodiments, the compound of formula (I) has structure (IA):

[0180]

[0181] In other embodiments, the compound of formula (I) has the structure (IB):

[0182]

[0183] In one embodiment, the compound is a compound of any of the following formulas, or an enantiomer, mixture of enantiomers, or tautomer, or a pharmaceutically acceptable salt thereof:

[0184]

[0185]

[0186] In some embodiments, R2 is independently selected from the group consisting of: H, CN, methyl, ethyl, isopropyl, chloro, methoxy, trifluoromethyl, 2-fluoroethyl, difluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, cyclopropylmethyl, cyclobutyl, and oxetane.

[0187] In some embodiments, R3 is selected from the group consisting of: H, fluorine, chloro, bromine, CN, methoxy, difluoromethyl, trifluoromethyl, methyl, and ethyl.

[0188] In some embodiments, the compounds are selected from the group consisting of:

[0189]

[0190] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0191] In some embodiments, the compounds are selected from the group consisting of:

[0192]

[0193] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0194] In some embodiments, the compounds are selected from the group consisting of:

[0195]

[0196]

[0197] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0198] In some embodiments, the compounds are selected from the group consisting of:

[0199]

[0200] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0201] In some embodiments, the compounds are selected from the group consisting of:

[0202]

[0203] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0204] In some embodiments, the compounds are selected from the group consisting of:

[0205]

[0206]

[0207] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0208] In some embodiments, the compounds are selected from the group consisting of:

[0209]

[0210]

[0211] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0212] In some embodiments, the compounds are selected from the group consisting of:

[0213]

[0214] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0215] In some embodiments, the compounds are selected from the group consisting of:

[0216]

[0217] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0218] In some embodiments, the compounds are selected from the group consisting of:

[0219]

[0220]

[0221] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0222] In some embodiments, the compounds are selected from the group consisting of:

[0223]

[0224]

[0225] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0226] In some embodiments, the compounds are selected from the group consisting of:

[0227]

[0228] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0229] In some embodiments, the compounds are selected from the group consisting of:

[0230]

[0231] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0232] In some embodiments, the compounds are selected from the group consisting of:

[0233]

[0234]

[0235] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0236] In some embodiments, the compounds are selected from the group consisting of:

[0237]

[0238] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0239] In some embodiments, the compounds are selected from the group consisting of:

[0240]

[0241] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0242] In some embodiments, the compounds are selected from the group consisting of:

[0243]

[0244] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0245] In some embodiments, the compounds are selected from the group consisting of:

[0246]

[0247] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0248] In some embodiments, the compounds are selected from the group consisting of:

[0249]

[0250]

[0251] In some embodiments, the compounds are selected from the group consisting of:

[0252]

[0253] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0254] In some embodiments, the compounds are selected from the group consisting of:

[0255]

[0256]

[0257] In some embodiments, the compounds are selected from the group consisting of:

[0258]

[0259] In some embodiments, the compounds are selected from the group consisting of:

[0260]

[0261]

[0262] In some embodiments, the compounds are selected from the group consisting of:

[0263]

[0264]

[0265] In some embodiments, the compounds are selected from the group consisting of:

[0266]

[0267] In some embodiments, the compounds are selected from the group consisting of:

[0268]

[0269] In some embodiments, the compounds are selected from the group consisting of:

[0270] In some embodiments, the compounds are selected from the group consisting of:

[0271]

[0272] In some embodiments, the compounds are selected from the group consisting of:

[0273]

[0274] In some embodiments, the compounds are selected from the group consisting of:

[0275]

[0276] In some embodiments, the compounds are selected from the group consisting of:

[0277]

[0278] In some embodiments, the compounds are selected from the group consisting of:

[0279]

[0280] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0281] In some embodiments, the compounds are selected from the group consisting of:

[0282]

[0283] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0284] In some embodiments, the compounds are selected from the group consisting of:

[0285]

[0286]

[0287] Or its enantiomers, mixtures of enantiomers or tautomers, or pharmaceutically acceptable salts thereof.

[0288] In some embodiments, the compound is selected from the group consisting of:

[0289]

[0290] Or its pharmaceutically acceptable salt.

[0291] In one implementation, the compounds in Table 1 are provided herein:

[0292] Table 1.

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305] Or its pharmaceutically acceptable salt.

[0306] For any compound in Table 1 that has a chiral center due to the presence of non-hydrogen R1, the R-enantiomers, S-enantiomers, and racemic compounds of this compound are specifically provided herein, even if not specifically shown in Table 1.

[0307] In one embodiment, a pharmaceutically acceptable salt of a compound of formula (I) is provided herein. In one embodiment, a pharmaceutically acceptable salt of any of the compounds in Table 1 is provided herein.

[0308] In some embodiments, the pharmaceutically acceptable salt of the compound is selected from the group consisting of: alkylammonium salts, dialkylammonium salts, trialkylammonium salts, tetraalkylammonium salts, L-arginine salts, benzylamine salts, benzathine salts, betaine salts, calcium hydroxide salts, choline salts, dimethylethanolamine salts, diethanolamine salts, diethylamine salts, 2-(diethylamino)ethanol salts, ethanolamine salts, ethylenediamine salts, N-methylglucosamine salts, hydrabamine salts, 1H-imidazolium salts, lithium salts, L-lysine salts, magnesium salts, 4-(2-hydroxyethyl)morpholine salts, piperazine salts, potassium salts, 1-(2-hydroxyethyl)pyrrolidine salts, sodium salts, triethanolamine salts, tromethamine salts, Na salts, Ca salts, K salts, Mg salts, and Zn salts.

[0309] In a specific implementation plan, the pharmaceutically acceptable salt is a solvate selected from the group consisting of water, methanol, ethanol, and dimethylformamide.

[0310] In some embodiments, the compound is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

[0311] In specific embodiments, the composition is selected from the group consisting of tablets, capsules, granules, lyophilized agents for reconstitution, powders, solutions, syrups, suppositories, injections, transdermal delivery systems, and solutions suitable for topical application.

[0312] How to use

[0313] This document provides methods for treating cancer, which include administering compounds of the present disclosure, such as compounds of formula (I), or enantiomers thereof, mixtures of enantiomers, or tautomers thereof, or pharmaceutically acceptable salts thereof.

[0314] Cancer is a disease caused by uncontrolled cell proliferation due to changes in certain genes. Some of these changes occur in genes encoding receptor tyrosine kinases (RTKs), a family of membrane-bound proteins that can transmit signals from outside the cell to promote cell survival, growth, and proliferation. Abnormal RTK activation leads to excessive cell growth, which in turn leads to cancer. Typically, RTKs contain an N-terminal domain that binds extracellular ligands, a transmembrane domain, and a C-terminal kinase domain that catalyzes intracellular signal transduction.

[0315] In some embodiments, the compound of formula (I) is an inhibitor of human ROS1. ROS1 is an RTK encoded by the ROS1 gene. The ligands and biological functions of human ROS1 are not well understood, but its homologues in some other species have been shown to bind extracellular ligands and stimulate cell differentiation. For example, mouse ROS1 is essential for male gamete maturation and reproduction. In humans, ROS1 chromosomal rearrangements are a well-proven cause of cancer, accounting for 1–2% of non-small cell lung cancer (NSCLC) and subsets of many other cancers. These rearrangements result in the fusion of the C-terminus of ROS1 with the N-terminus of various partner proteins, the most common of which is CD74. ROS1 fusions possess constitutive kinase activity, which drives tumor growth via the MAPK, PI3K, and JAK / STAT signaling pathways. Small molecule tyrosine kinase inhibitors (TKIs) have been used to target ROS1 fusions in cancer, including crizotinib and entrectinib. Crizotinib was the first FDA-approved TKI for the treatment of ROS1-positive NSCLC, with an overall response rate of 60-80% and a median progression-free survival of 9-19 months. Despite initial responses, most patients develop resistance to crizotinib and relapse. The primary mechanism of resistance is the G2032R mutation at the solvent front, which significantly reduces the affinity for crizotinib. The FDA has not yet approved inhibitors active against the ROS1-G2032R fusion, indicating a need in this field.

[0316] In some embodiments, the compound of formula (I) is an inhibitor of human degenerative lymphoma kinase (ALK). ALK, also known as differentiation cluster 246 (CD246), is an RTK encoded by the ALK gene. ALK and ROS1 are evolutionarily related; both belong to the insulin receptor superfamily, and their kinase domains share approximately 80% sequence similarity. Several human ALK ligands have been identified, including pleiotropic protein and metaphase I growth factor. While the role of ALK in humans remains inconclusive, much evidence from mouse studies suggests it is crucial for nervous system development. Like ROS1, ALK chromosomal rearrangements also result in constitutively active fusion proteins that promote oncogenic transformation via MAPK, JAK / STAT, or other signaling pathways. ALK rearrangements account for 3–5% of NSCLC, approximately half of anaplastic large cell lymphoma (ALCL), and subsets of many other cancers, with the major fusions being EML4-ALK in NSCLC and NPM1-ALK in ALCL. Oncogenic point mutations and ALK amplification were also observed, although at a much lower frequency than translocations. Crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are FDA-approved TKIs for the treatment of ALK-positive NSCLC and other cancers, both as first-line therapy and after prior therapy. For example, crizotinib has an overall response rate of 60–80% and a median progression-free survival of 8–11 months, comparable to its activity in ROS1-positive NSCLC. Despite initial responses, many resistance mutations have emerged in the aforementioned FDA-approved TKIs. Some of these mutations (such as the combination of the L1196M gatekeeper and G1202R solvent front mutations) are resistant to all approved drugs. There is a need in the art for novel treatments for ALK-positive cancers with resistance mutations.

[0317] In other embodiments, the compound of formula (I) is an inhibitor of human tropomyosin receptor kinase (TRK). The TRK family includes receptor tyrosine kinases TRKA, TRKB, and TRKC, encoded by the genes NTRK1, NTRK2, and NTRK3, respectively. Each TRK is activated by a distinct but overlapping set of neurotrophic factor ligands such as NGF, BDNF, and NT-3. All TRKs regulate similar downstream signaling pathways, consistent with sequence divergence in the ligand-binding domain but convergence (90% similarity) in the kinase domain. TRKs play important roles in the nervous system of developing and adult mammals by regulating processes such as memory, movement, pain, and proprioception. Like ROS1 and ALK, NTRK rearrangements produce constitutively active TRK fusions that drive oncogenic transformation via MAPK, PI3K, and other pathways. TRK fusions have been found in many cancers and account for more than 80% of cases in secretory breast cancer, breast-like secretory carcinomas, infantile fibrosarcoma, and congenital mesodermal nephroma. Therefore, inhibiting TRK is beneficial for treating cancers that express TRK fusions.

[0318] Many existing ROS1 and ALK inhibitors also exhibit effective inhibition of naturally occurring, non-oncogenic TRK. This is a substantial drawback because naturally occurring TRK plays a vital role in the nervous system, and unintentional inhibition of naturally occurring TRK is associated with adverse reactions including dizziness, ataxia, gait disturbances, sensory abnormalities, weight gain, and cognitive changes. There is a need in the art for novel therapies that selectively target non-mutated and / or mutant forms of ROS1 and / or ALK without impairing TRK.

[0319] In one embodiment, this document provides a method for reducing ROS1 or ALK levels in cells, comprising contacting cells with compounds or pharmaceutical compositions or combinations of drugs provided herein. In one embodiment, such contact occurs in cells of mammals such as humans. In one embodiment, such contact occurs in cells of a human patient suffering from the cancer described herein.

[0320] In one embodiment, the compound provided herein selectively inhibits ROS1. In one embodiment, the compound selectively inhibits ROS1 relative to ALK. As a non-limiting example, the selectivity ratio may be greater than about 1.5 times, greater than about 2 times, greater than about 3 times, greater than about 4 times, greater than about 5 times, greater than about 10 times, greater than about 20 times, greater than about 30 times, greater than about 50 times, or greater than about 100 times, wherein the selectivity can be determined by IC50. 50 The ratio of values ​​and other methods are used to measure it. In one implementation, the selectivity of ROS1 relative to ALK is measured by IC of ALK. 50 Value and IC of ROS1 50It is measured by the ratio of values.

[0321] In one embodiment, the compound selectively inhibits ROS1 relative to TRK (e.g., TRKA, TRKB, and / or TRBC). As a non-limiting example, the selectivity ratio can be greater than about 5-fold, greater than about 10-fold, greater than about 50-fold, greater than about 100-fold, greater than about 200-fold, greater than about 400-fold, greater than about 600-fold, greater than about 800-fold, greater than about 1000-fold, greater than about 1500-fold, greater than about 2000-fold, greater than about 5000-fold, greater than about 10,000-fold, or greater than about 20,000-fold, wherein the selectivity can be determined by IC50. 50 The ratio of values ​​and other methods are used to measure it. In one implementation, the selectivity of ROS1 relative to TRK is measured by the IC of TRK. 50 Value and IC of ROS1 50 It is measured by the ratio of values.

[0322] In one embodiment, the compound provided herein selectively inhibits ALK. In one embodiment, the compound selectively inhibits ALK relative to ROS1. As a non-limiting example, the selectivity ratio may be greater than about 1.5 times, greater than about 2 times, greater than about 3 times, greater than about 4 times, greater than about 5 times, or greater than about 10 times, wherein the selectivity can be determined by IC50. 50 The ratio of values ​​and other methods are used to measure it. In one implementation, the selectivity of ALK relative to ROS1 is measured by the IC of ROS1. 50 Value and IC of ALK 50 It is measured by the ratio of values.

[0323] In one embodiment, the compound selectively inhibits ALK relative to TRK (e.g., TRKA, TRKB, and / or TRBC). As a non-limiting example, the selectivity ratio can be greater than about 5-fold, greater than about 10-fold, greater than about 50-fold, greater than about 100-fold, greater than about 200-fold, greater than about 400-fold, greater than about 600-fold, greater than about 800-fold, greater than about 1000-fold, greater than about 1500-fold, greater than about 2000-fold, greater than about 5000-fold, or greater than about 10,000-fold, wherein the selectivity can be determined by IC50. 50 The ratio of values ​​and other methods are used to measure it. In one implementation, the selectivity of ALK relative to TRK is measured by the IC of TRK. 50 Value and IC of ALK 50 It is measured by the ratio of values.

[0324] In one embodiment, the compound selectively inhibits ROS1 and ALK relative to TRK (e.g., TRKA, TRKB, and / or TRBC). As a non-limiting example, the selectivity ratio can be greater than about 5-fold, greater than about 10-fold, greater than about 50-fold, greater than about 100-fold, greater than about 200-fold, greater than about 400-fold, greater than about 600-fold, greater than about 800-fold, greater than about 1000-fold, greater than about 1500-fold, greater than about 2000-fold, greater than about 5000-fold, greater than about 10,000-fold, or greater than about 20,000-fold, wherein the selectivity can be determined by IC50. 50 The ratio of values ​​and other methods are used to measure them. In one implementation, the selectivity of ROS1 and ALK relative to TRK is measured by the IC of TRK. 50 Values ​​and IC values ​​for ROS1 and ALK 50 It is measured by the ratio of values.

[0325] In one embodiment, this document provides a method for selectively inhibiting ROS1 relative to ALK, wherein the inhibition occurs in cells. In one embodiment, this document provides a method for selectively inhibiting ROS1 relative to TRK (e.g., TRKA, TRKB, and / or TRBC), wherein the inhibition occurs in cells. In one embodiment, the method includes contacting ROS1 with an effective amount of the compound provided herein. In one embodiment, this contact occurs in cells. In one embodiment, this contact occurs in cells of mammals such as humans. In one embodiment, this contact occurs in cells of a human patient suffering from the cancer provided herein.

[0326] In one embodiment, this document provides a method for selectively inhibiting ROS1 relative to ALK, wherein the inhibition occurs in a subject suffering from cancer, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein. In some embodiments, this document provides a method for treating a subject suffering from ROS1-related cancer, the method comprising selectively inhibiting ROS1 relative to ALK by administering to the subject an amount of a compound or pharmaceutical composition provided herein, wherein the amount is sufficient to selectively inhibit ROS1 relative to ALK.

[0327] In one embodiment, this document provides a method for selectively inhibiting ROS1 relative to TRKs (e.g., TRKA, TRKB, and / or TRBC), wherein the inhibition occurs in a subject with cancer, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein. In some embodiments, this document provides a method for treating a subject with ROS1-related cancer, the method comprising selectively inhibiting ROS1 relative to TRKs (e.g., TRKA, TRKB, and / or TRBC) by administering to the subject an amount of a compound or pharmaceutical composition provided herein, wherein the amount is sufficient to selectively inhibit ROS1 relative to TRKs (e.g., TRKA, TRKB, and / or TRBC).

[0328] In one embodiment, this document provides a method for selectively inhibiting ALK relative to ROS1, wherein the inhibition occurs in cells. In one embodiment, this document provides a method for selectively inhibiting ALK relative to TRK (e.g., TRKA, TRKB, and / or TRBC), wherein the inhibition occurs in cells. In one embodiment, the method includes contacting ALK with an effective amount of a compound provided herein. In one embodiment, this contact occurs in cells. In one embodiment, this contact occurs in cells of mammals such as humans. In one embodiment, this contact occurs in cells of a human patient suffering from a cancer provided herein.

[0329] In one embodiment, this document provides a method for selectively inhibiting ALK relative to ROS1, wherein the inhibition occurs in a subject suffering from cancer, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein. In some embodiments, this document provides a method for treating a subject suffering from ALK-related cancer, the method comprising selectively inhibiting ALK relative to ROS1 by administering to the subject an amount of a compound or pharmaceutical composition provided herein, wherein the amount is sufficient to selectively inhibit ALK relative to ROS1.

[0330] In one embodiment, this document provides a method for selectively inhibiting ALK relative to TRKs (e.g., TRKA, TRKB, and / or TRBC), wherein the inhibition occurs in a subject with cancer, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein. In some embodiments, this document provides a method for treating a subject with ALK-related cancer, the method comprising selectively inhibiting ALK relative to TRKs (e.g., TRKA, TRKB, and / or TRBC) by administering to the subject an amount of a compound or pharmaceutical composition provided herein, wherein the amount is sufficient to selectively inhibit ALK relative to TRKs (e.g., TRKA, TRKB, and / or TRBC).

[0331] As used herein, unless otherwise stated, suppression of ROS1 includes suppression of wild-type ROS1 or its mutations; suppression of ALK includes suppression of wild-type ALK or its mutations; and suppression of TRK includes suppression of wild-type TRK or its mutations.

[0332] Cancers that can be treated using the methods disclosed herein include, but are not limited to, lung cancer (e.g., non-small cell lung cancer), inflammatory myofibroblastic tumor, ovarian cancer (e.g., serous ovarian cancer), melanoma (e.g., Spitz nevus-like melanoma), glioblastoma, cholangiocarcinoma (e.g., cholangiocarcinoma), gastric cancer, colorectal cancer, angiosarcoma, anaplastic large cell lymphoma, diffuse large B-cell lymphoma, large B-cell lymphoma, esophageal cancer (e.g., esophageal squamous cell carcinoma), renal cancer (e.g., renal medullary carcinoma or renal cell carcinoma), breast cancer (e.g., triple-negative breast cancer), thyroid cancer (e.g., papillary thyroid carcinoma), neuroblastoma, epithelioid hemangioendothelioma, colon cancer, and Spitz nevus-like tumors.

[0333] Cancers treated by the methods of this disclosure include cancers originating from one or more oncogenes selected from ROS1, ALK, TRKA, TRKB, and TRKC. In some embodiments, cancers treated by the methods of this disclosure include cancers resistant to treatment against one or more oncogenes selected from ROS1, ALK, TRKA, TRKB, and TRKC.

[0334] In one embodiment, the cancer in the methods provided herein is anaplastic lymphoma kinase positive (ALK+). As used herein, unless otherwise stated, “ALK-positive” (ALK+) cancer, disease, or condition refers to a cancer, disease, or condition characterized by inappropriate overexpression of the ALK gene and / or the presence of mutations in the ALK gene. In one embodiment, the mutation alters the biological activity of the ALK nucleic acid molecule or polypeptide. As used herein, unless otherwise stated, a “mutation” or “mutant” of ALK comprises one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications of an amino acid or nucleotide sequence or fragment thereof of ALK. As used herein, unless otherwise stated, an ALK “rearrangement” refers to a genetic translocation involving the ALK gene that can produce an ALK fusion gene and / or an ALK fusion protein. ALK fusions may also comprise one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications or fragments thereof, provided that the mutant retains kinase phosphorylation activity.

[0335] In one embodiment, the ALK mutation includes one or more ALK point mutations. In some embodiments, the cancer treated by the methods of this disclosure includes one or more mutations in the ALK kinase. In one embodiment, the one or more ALK point mutations are selected from point mutations at L1152, C1156, I1171, F1174, V1180, L1196, L1198, G1202, D1203, S1206, E1210, F1245, G1269, and R1275. In one embodiment, one or more ALK point mutations are selected from G1202R, G1202K, L1196M, G1269A, C1156Y, I1171T, I1171N, I1171S, F1174L, V1180L, S1206Y, E1210K, 1151Tins, F1174C, G1202del, D1203N, S1206Y, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, and F1245V. In one embodiment, the ALK mutation is G1202R. In one embodiment, the ALK mutation is L1196M. In one embodiment, the ALK mutation is G1269A. In one embodiment, the ALK mutation is L1198F. In one embodiment, the ALK mutation is G1202R co-mutated with one or more mutations selected from L1196M, G1269A, and L1198F. In one embodiment, the ALK mutation is a double mutation of G1202R / L1196M. In one embodiment, the ALK mutation is a double mutation of G1202R / G1269A. In one embodiment, the ALK mutation is a double mutation of G1202R / L1198F.

[0336] In one embodiment, the ALK mutation includes one or more ALK rearrangements (in one embodiment, a rearrangement). In one embodiment, the ALK mutation includes one or more ALK fusions (in one embodiment, a fusion). In some embodiments, cancers treated by the methods of this disclosure include ALK fusions. In one embodiment, the ALK fusion is a fusion with one of the following fusion partners: EML4, TMP1, WDCP, GTF2IRD1, TPM3, TPM4, CLTC, LMNA, PRKAR1A, RANBP2, TFG, FN1, KLC1, VCL, STRN, HIP1, NPM1, DCTN1, SQSTM1, TPR, CRIM1, PTPN3, FBXO36, ATIC, and KIF5B. In one embodiment, the ALK mutation is a fusion between the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK tyrosine kinase domain, EML4-ALK. EML4-ALK has many variants, which differ in their breakpoint connections, with variant 1 (v1) and variant 3 (v3) being the most common in clinical practice.

[0337] In one embodiment, the ALK mutation includes an ALK rearrangement and one or more ALK point mutations. In one embodiment, the ALK mutation is EML4-ALK wt (variant 1). In one embodiment, the ALK mutation is EML4-ALKG1202R (variant 1). In one embodiment, the ALK mutation is EML4-ALK L1196M / G1202R (variant 1). In one embodiment, the ALK mutation is EML4-ALK G1202R / G1269A (variant 1). In one embodiment, the ALK mutation is EML4-ALK G1202R / L1198F (variant 1).

[0338] In one implementation, ALK+ cancer is determined by an FDA-approved test or other tests known in the art. Tests that can be used include, for example, FoundationOne CDx. TM(F1CDx) (a sequencing-based in vitro diagnostic device for detecting substitution, insertion, and deletion variations (indels) and copy number changes (CNAs) in 324 genes and selecting gene rearrangements and genomic features (including microsatellite instability (MSI) and tumor mutational burden (TMB)) using DNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissue samples; VEN TANA ALK (D5F3) CDx assay (qualitative detection of intermediate-degenerative lymphoma kinase (ALK) protein in formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue stained with BenchMarkXT or BenchMark ULTRA automated staining system); and Vysis ALK Break The ApartFISH probe kit test (a qualitative test for detecting ALK gene rearrangements in formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue samples by fluorescence in situ hybridization (FISH). In one embodiment, the test is a fluorescence in situ hybridization (FISH) test, such as the Vysis ALK Break Apart FISH probe kit test. Additional information on FDA-approved tests can be found, for example, at https: / / www.fda.gov / MedicalDevices / ProductsandMedicalProcedures / InVitroDiagnostics / ucm303030.htm; and additional information on the Vysis ALK Break Apart FISH probe kit can be found, for example, at https: / / www.molecular.abbott / us / en / products / oncology / vysis-alk-break-apart-fish-probe-kit; the entire contents of these references are incorporated herein by reference.

[0339] A method for treating a subject with cancer (e.g., ALK-positive cancer) is also provided, comprising: determining whether cancer cells in a sample obtained from a subject with cancer who has previously been treated with a first ALK inhibitor have one or more ALK inhibitor resistance mutations; and if the subject has cancer cells with one or more ALK inhibitor resistance mutations, administering a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof to the subject as a monotherapy or in combination with another anticancer agent. In some embodiments, one or more ALK inhibitor resistance mutations confer increased resistance to treatment with a first ALK inhibitor. In some embodiments, one or more ALK inhibitor resistance mutations include one or more ALK inhibitor resistance mutations. For example, resistance mutations to one or more ALK inhibitors may include substitutions at one or more of the following amino acid positions: 1202, 1196, 1269, 1156, 1171, 1174, 1180, 1206, 1210, 1151, 1174, 1203, 1206, 1152, 1196, 1198, 1275, 1152, 1156, and 1245, such as G1202R, L1196M, and G1269. A, C1156Y, I1171T, I1171N, I1171S, F1174L, V1180L, S1206Y, E1210K, 1151Tins, F1174C, G1202del, D1203N, S1206Y, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, and F1245V. In some embodiments, the other anticancer agent is any anticancer agent known in the art. For example, the other anticancer agent may be another ALK inhibitor (e.g., a second ALK inhibitor).

[0340] In one embodiment, the cancer in the methods provided herein is a ROS1-positive (ROS1+) cancer. As used herein, unless otherwise stated, “ROS1-positive (ROS1+) cancer, disease, or condition” refers to a cancer, disease, or condition characterized by inappropriate high expression of the ROS1 gene and / or the presence of mutations in the ROS1 gene. In one embodiment, the mutation alters the biological activity of the ROS1 nucleic acid molecule or polypeptide. As used herein, unless otherwise stated, a “mutation” or “mutant” of ROS1 comprises one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications of an amino acid or nucleotide sequence or fragment thereof of ROS1. As used herein, unless otherwise stated, a “ROS1 rearrangement” refers to a genetic translocation involving the ROS1 gene that can produce a ROS1 fusion gene and / or a ROS1 fusion protein. ROS1 fusions may also include one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications or fragments thereof, provided that the mutant retains kinase phosphorylation activity.

[0341] In one embodiment, the ROS1 mutation includes one or more ROS1 point mutations. In some embodiments, the cancer treated by the methods of this disclosure includes one or more mutations in the ROS1 kinase. In one embodiment, the one or more ROS1 point mutations are selected from point mutations at E1935, L1947, L1951, G1971, E1974, L1982, S1986, F2004, E2020, L2026, G2032, D2033, C2060, F2075, L2086, V2089, V2098, G2101, D2113, and L2155. In one embodiment, one or more ROS1 point mutations are selected from G2032R, G2032K, D2033N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, and L2086F. In one embodiment, the ROS1 mutation is G2032R. In one embodiment, the ROS1 mutation is S1986F. In one embodiment, the ROS1 mutation is S1986Y. In one embodiment, the ROS1 mutation is L2026M. In one embodiment, ROS1 is mutated to D2033N. In one embodiment, ROS1 is mutated to L2086F. In one embodiment, ROS1 is mutated to F2004C. In one embodiment, ROS1 is mutated to F2004V. In one embodiment, ROS1 is mutated to G2101A. In one embodiment, ROS1 is mutated to L1982F. In one embodiment, ROS1 is mutated to G2032R and co-mutated with one or more of S1986F, S1986Y, F2004C, F2004V, L2026M, or D2033N.

[0342] In one embodiment, the ROS1 mutation comprises one or more ROS1 rearrangements (in one embodiment, a rearrangement). In one embodiment, the ROS1 mutation comprises one or more ROS1 fusions (in one embodiment, a fusion). In some embodiments, cancers treated by the methods of this disclosure include ROS1 fusions. In one embodiment, the ROS1 fusion is a fusion with one of the following fusion partners: SLC34A2, CD74, TPM3, SDC4, EZR, LRIG3, KDELR2, CEP72, CLTL, CTNND2, GOPC (e.g., GOPC-S, GOPC-L), GPRC6A, LIMA1, LRIG3, MSN, MYO5C, OPRM1, SLC6A17SLMAP, SRSF6, TFG, TMEM106B, The following are listed: TPD52L1, ZCCHC8, CCDC6, CAPRIN1, CEP85L, CHCHD3, CLIP1, EEF1G, KIF21A, KLC1, SART3, ST13, TRIM24, ERC1, FIP1L1, HLAA, KIAA1598, MYO5A, PPFIBP1, PWWP2A, FN1, YWHAE, CCDC30, NCOR2, NFKB2, APOB, PLG, RBP4, and GOLGB1. In one embodiment, the ROS1 fusion is a CD74-ROS1 fusion. In one embodiment, the ROS1 fusion is an SDC4-ROS1 fusion. In one embodiment, the ROS1 fusion is an EZR-ROS1 fusion. In one embodiment, the ROS1 fusion is an SLC34A2-ROS1 fusion. In one embodiment, the ROS1 fusion is a GOPC-ROS1 fusion (e.g., GOPC-ROS1-S, GOPC-ROS1-L). In another embodiment, the ROS1 fusion is a CEP85L-ROS1 fusion.

[0343] In one embodiment, the ROS1 mutation includes a ROS1 rearrangement and one or more ROS1 point mutations. In one embodiment, the ROS1 mutation includes one or more ROS1 rearrangements from CD74-ROS1, EZR-ROS1, SLC34A2-ROS1, GOPC-ROS1 (e.g., GOPC-ROS1-S, GOPC-ROS1-L), and CEP85L-ROS1, and one or more ROS1 point mutations selected from F2004C, F2004V, and G2032R. In one embodiment, the ROS1 mutation includes one or more ROS1 rearrangements from CD74-ROS1, EZR-ROS1, and SLC34A2-ROS1, and a ROS1 point mutation from G2101A.

[0344] In one embodiment, ROS1 is mutated to CD74-ROS1 F2004C. In one embodiment, ROS1 is mutated to CD74-ROS1 F2004V. In one embodiment, ROS1 is mutated to CD74-ROS1 G2101A. In one embodiment, ROS1 is mutated to CD74-ROS1 G2032R. In one embodiment, ROS1 is mutated to CD74-ROS1 S1986F. In one embodiment, ROS1 is mutated to CD74-ROS1 L2026M. In one embodiment, ROS1 is mutated to CD74-ROS1 D2033N. In one embodiment, ROS1 is mutated to EZR-ROS1 F2004C. In one embodiment, ROS1 is mutated to EZR-ROS1 F2004V. In one embodiment, ROS1 is mutated to EZR-ROS1 G2101A. In one embodiment, ROS1 is mutated to EZR-ROS1 G2032R. In one embodiment, ROS1 is mutated to SLC34A2-ROS1 F2004C. In one embodiment, ROS1 is mutated to SLC34A2-ROS1 F2004V. In one embodiment, ROS1 is mutated to SLC34A2-ROS1 G2101A. In one embodiment, ROS1 is mutated to SLC34A2-ROS1 G2032R. In one embodiment, ROS1 is mutated to GOPC-ROS1 F2004C (e.g., GOPC-ROS1-S F2004C, GOPC-ROS1-LF2004C). In one embodiment, ROS1 is mutated to GOPC-ROS1 F2004V (e.g., GOPC-ROS1-S F2004V, GOPC-ROS1-L F2004V). In one embodiment, ROS1 is mutated to GOPC-ROS1 G2032R (e.g., GOPC-ROS1-SG2032R, GOPC-ROS1-L G2032R). In one embodiment, ROS1 is mutated to CEP85L-ROS1 F2004C. In one embodiment, ROS1 is mutated to CEP85L-ROS1 F2004V. In one embodiment, ROS1 is mutated to CEP85L-ROS1 G2032R. In one embodiment, ROS1 is mutated to GOPC-ROS1 L1982F (e.g., GOPC-ROS1-S L1982F, GOPC-ROS1-LL1982F). In one embodiment, ROS1 is mutated to CD74-ROS1 L1982F.

[0345] In one implementation, ROS1+ cancer is determined by an FDA-approved test or other tests known in the art. Tests that can be used include, for example, Oncomine developed by Thermo Fisher Scientific. TM Dx Target test (a qualitative in vitro diagnostic test that uses targeted high-throughput parallel sequencing technology, employing the Ion PGM Dx system to detect sequence variations in 23 genes in DNA and RNA isolated from formalin-fixed paraffin-embedded tumor (FFPE) tissue samples from patients with non-small cell lung cancer (NSCLC); Vysis ROS1 Break Apart FISH probe kit (a qualitative test by fluorescence in situ hybridization (FISH) to detect rearrangements involving the ROS1 gene rearrangement at 6q22 in formalin-fixed paraffin-embedded (FFPE) NSCLC tissue samples); or RT real-time polymerase chain reaction (RT-PCR); or NGSNext Generation sequencing performed via a local diagnostic test.

[0346] A method for treating a subject with cancer (e.g., ROS1-positive cancer) is also provided, comprising: determining whether cancer cells in a sample obtained from a subject with cancer who has previously been treated with a first ROS1 inhibitor have one or more ROS1 inhibitor resistance mutations; and if the subject has cancer cells with one or more ROS1 inhibitor resistance mutations, administering a compound of formula (I) or a pharmaceutically acceptable salt or solvation thereof to the subject as a monotherapy or in combination with another anticancer agent. In some embodiments, one or more ROS1 inhibitor resistance mutations confer increased resistance of cancer cells or tumors to treatment with a first ROS1 inhibitor. In some embodiments, one or more ROS1 inhibitor resistance mutations include one or more ROS1 inhibitor resistance mutations. For example, resistance mutations to one or more ROS1 inhibitors may include substitutions at one or more of the following amino acid positions: 2032, 2033, 1986, 2026, 1951, 1935, 1947, 1971, 1974, 1982, 2004, 2020, 2060, 2075, 2089, 2098, 2101, 2113, 2155, 2032, and 2086, such as G2032R, D203. 3N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, L2032K, and L2086F. In some embodiments, the other anticancer agent is any anticancer agent known in the art. For example, the other anticancer agent may be another ROS1 inhibitor (e.g., a second ROS1 inhibitor).

[0347] In one embodiment, the compound provided herein is a compound that penetrates the CNS. In one embodiment, after administration of an effective amount of the compound provided herein (e.g., orally or intravenously), the compound is able to penetrate the CNS (e.g., the blood-brain barrier) and reach concentrations in the CNS (e.g., the brain) that are still sufficient to inhibit (e.g., selectively inhibit) ROS1 or ALK or both.

[0348] In one embodiment, this document provides a method for treating CNS metastases of cancer, comprising administering to a subject in need an effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the CNS metastasis is a brain metastasis. In one embodiment, the cancer is a ROS1+ cancer. In one embodiment, the cancer is an ALK+ cancer.

[0349] In some embodiments, the compound is an inhibitor of human tropomyosin receptor kinases A, B, or C. In some embodiments, the compound for inhibiting mutant or non-mutated ROS1 or ALK has an IC50 value. 50 The IC50 value of compounds used to inhibit wild-type tropomyosin receptor kinases A, B, or C does not exceed the limit. 50 One-fifth. TRK inhibition, particularly in the central nervous system (CNS), has been associated with adverse reactions, including dizziness / ataxia / gait disturbances, paresthesia, weight gain, and cognitive changes.

[0350] In some embodiments, a method is provided to minimize adverse events in subjects requiring treatment for cancer (e.g., ROS1-positive or ALK-positive cancer), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), its enantiomers, mixtures of enantiomers, or tautomers, or a pharmaceutically acceptable salt thereof, and wherein said method minimizes adverse events associated with TRK inhibitors. In some embodiments, the cancer is ROS1-related cancer or ALK-related (or ALK+) cancer. In some embodiments, the adverse events are TRK-related CNS adverse events.

[0351] As used herein, “minimizing” adverse events means reducing the incidence of adverse events in a subject or patient population compared to the typical incidence of adverse events in subjects or patient populations treated with TRK inhibitors (e.g., entrectinib, repotrectinib, or lorlatinib). In some embodiments, the incidence of adverse events refers to the frequency or percentage of a specific adverse event in a subject or patient population. In some embodiments, the incidence of adverse events refers to the total number of adverse events experienced by an individual subject. In some embodiments, minimizing adverse events means minimizing TRK-related CNS adverse events. In some embodiments, minimizing TRK-related CNS adverse events means that less than 40% of the patient population has TRK-related CNS adverse events. In some embodiments, minimizing TRK-related CNS adverse events means that less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5% of the patient population has TRK-related CNS adverse events. In some implementations, minimizing TRK-related CNS adverse events means that less than 12% of the patient population has more than one TRK-related CNS adverse event. In some implementations, minimizing TRK-related CNS adverse events means that less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3% of the patient population has more than one TRK-related CNS adverse event.

[0352] In some implementations, TRK-related CNS adverse events refer to one or more of the following: dizziness, ataxia, gait disturbance, paresthesia, weight gain, overeating, paresthesia, abnormal movement, cognitive changes, speech effects (e.g., dysarthria, bradysphagia, or language disorder), mood disorders (e.g., irritability, anxiety, depression, emotional instability, personality changes, mood swings, affective disorders, aggression, agitation, mood changes, depressive mood, euphoria, or mania), and cognitive impairments (e.g., impaired memory, cognitive impairment, amnesia, confusion, attention deficit, mental disorder, psychological harm, attention deficit / hyperactivity disorder, dementia, or dyslexia).

[0353] In one embodiment, this document provides a method intended for preventing or limiting TRK-related CNS side effects or adverse events in cancer treatment, comprising administering to a subject in need an effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the method prevents the occurrence of TRK-related CNS adverse events. In one embodiment, the method limits the frequency of TRK-related CNS adverse events. In one embodiment, the method limits the severity of TRK-related side effects. In one embodiment, this document provides a method for treating CNS metastases of cancer with reduced TRK-related side effects, the method comprising administering to a subject in need an effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof. In one implementation, a reduction / limitation / prevention of CNS side effects or adverse events compared to standard of care is determined in a statistical sample, such as an approved ROS1 and / or ALK inhibitor (e.g., crizotinib, entrectinib, lorlatinib, or loprotinib) for ROS1+ and / or ALK+ cancers. In one implementation, TRK-related side effects are TRKB-related CNS side effects. In one implementation, TRK-related CNS side effects or adverse events are dizziness, ataxia, gait disturbance, paresthesia, weight gain, cognitive impairment, mood disturbance, or sleep disturbance.

[0354] In one embodiment, this document provides a method for treating cancer, comprising administering to a subject in need a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer is ROS1-related cancer. In one embodiment, the cancer is ROS1+ cancer. In one embodiment, the cancer is ALK-related cancer. In one embodiment, the cancer is ALK+ cancer. In one embodiment, the cancer is identified as ROS1+. In one embodiment, the cancer is identified as ALK+.

[0355] In one embodiment, this document provides a method for treating ROS1+ cancer, comprising administering to a subject in need a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0356] In one embodiment, this document provides a method for treating ALK+ cancer, comprising administering to a subject in need a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0357] In one embodiment, this document provides a method for treating a subject's cancer, comprising: (i) identifying the subject's cancer as ROS1+, and (ii) administering to the subject a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0358] In one embodiment, this document provides a method for treating a subject's cancer, comprising: (i) identifying the subject's cancer as ALK+, and (ii) administering to the subject a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0359] In one implementation, the cancer (or ROS1+ cancer or ALK+ cancer) is a solid tumor. In another implementation, the cancer (or ROS1+ cancer or ALK+ cancer) is lung cancer (e.g., non-small cell lung cancer (NSCLC)), glioblastoma, inflammatory myofibroblastic tumor (IMT), bile duct cancer (e.g., cholangiocarcinoma), ovarian cancer (e.g., serous ovarian cancer), gastric cancer, colorectal cancer, angiosarcoma, melanoma (e.g., Spitz nevus-like melanoma), epithelioid angioendothelioma, esophageal cancer (e.g., esophageal squamous cell carcinoma (ESCC)), renal cancer (e.g., renal medullary carcinoma or renal cell carcinoma), breast cancer (e.g., triple-negative breast cancer), colon cancer, thyroid cancer (e.g., papillary thyroid carcinoma), Spitz nevus-like tumor, or neuroblastoma.

[0360] In one embodiment, the disease is lung cancer. In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is ROS1+ non-small cell lung cancer. In one embodiment, the cancer is ALK+ non-small cell lung cancer. In one embodiment, the cancer is relapsed or refractory non-small cell lung cancer. In one embodiment, the cancer is relapsed or refractory ROS1+ non-small cell lung cancer. In one embodiment, the cancer is relapsed or refractory ALK+ non-small cell lung cancer. In one embodiment, the cancer is newly diagnosed non-small cell lung cancer. In one embodiment, the cancer is newly diagnosed ROS1+ non-small cell lung cancer. In one embodiment, the cancer is newly diagnosed ALK+ non-small cell lung cancer.

[0361] In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is ROS1+ glioblastoma. In one embodiment, the cancer is ALK+ glioblastoma. In one embodiment, the cancer is relapsed or refractory glioblastoma. In one embodiment, the cancer is relapsed or refractory ROS1+ glioblastoma. In one embodiment, the cancer is relapsed or refractory ALK+ glioblastoma. In one embodiment, the cancer is newly diagnosed glioblastoma. In one embodiment, the cancer is newly diagnosed ROS1+ glioblastoma. In one embodiment, the cancer is newly diagnosed ALK+ glioblastoma.

[0362] In one embodiment, the cancer is IMT. In one embodiment, the cancer is ROS1+IMT. In one embodiment, the cancer is ALK+IMT. In one embodiment, the cancer is relapsed or refractory IMT. In one embodiment, the cancer is relapsed or refractory ROS1+IMT. In one embodiment, the cancer is relapsed or refractory ALK+IMT. In one embodiment, the cancer is newly diagnosed IMT. In one embodiment, the cancer is newly diagnosed ROS1+IMT. In one embodiment, the cancer is newly diagnosed ALK+IMT.

[0363] In one embodiment, the cancer is bile duct cancer. In another embodiment, the cancer is cholangiocarcinoma. In one embodiment, the cancer is ROS1+ bile duct cancer. In one embodiment, the cancer is ALK+ bile duct cancer. In one embodiment, the cancer is recurrent or refractory bile duct cancer. In one embodiment, the cancer is recurrent or refractory ROS1+ bile duct cancer. In one embodiment, the cancer is recurrent or refractory ALK+ bile duct cancer. In one embodiment, the cancer is newly diagnosed bile duct cancer. In one embodiment, the cancer is newly diagnosed ROS1+ bile duct cancer. In one embodiment, the cancer is newly diagnosed ALK+ bile duct cancer.

[0364] In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is ROS1+ ovarian cancer. In one embodiment, the cancer is ALK+ ovarian cancer. In one embodiment, the cancer is recurrent or refractory ovarian cancer. In one embodiment, the cancer is recurrent or refractory ROS1+ ovarian cancer. In one embodiment, the cancer is recurrent or refractory ALK+ ovarian cancer. In one embodiment, the cancer is newly diagnosed ovarian cancer. In one embodiment, the cancer is newly diagnosed ROS1+ ovarian cancer. In one embodiment, the cancer is newly diagnosed ALK+ ovarian cancer. In one embodiment, the ovarian cancer is serous ovarian cancer. In one embodiment, the ovarian cancer is high-grade serous ovarian cancer.

[0365] In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is ROS1+ gastric cancer. In one embodiment, the cancer is ALK+ gastric cancer. In one embodiment, the cancer is recurrent or refractory gastric cancer. In one embodiment, the cancer is recurrent or refractory ROS1+ gastric cancer. In one embodiment, the cancer is recurrent or refractory ALK+ gastric cancer. In one embodiment, the cancer is newly diagnosed gastric cancer. In one embodiment, the cancer is newly diagnosed ROS1+ gastric cancer. In one embodiment, the cancer is newly diagnosed ALK+ gastric cancer.

[0366] In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is ROS1+ colorectal cancer. In one embodiment, the cancer is ALK+ colorectal cancer. In one embodiment, the cancer is recurrent or refractory colorectal cancer. In one embodiment, the cancer is recurrent or refractory ROS1+ colorectal cancer. In one embodiment, the cancer is recurrent or refractory ALK+ colorectal cancer. In one embodiment, the cancer is newly diagnosed colorectal cancer. In one embodiment, the cancer is newly diagnosed ROS1+ colorectal cancer. In one embodiment, the cancer is newly diagnosed ALK+ colorectal cancer.

[0367] In one embodiment, the cancer is angiosarcoma. In one embodiment, the cancer is ROS1+ angiosarcoma. In one embodiment, the cancer is ALK+ angiosarcoma. In one embodiment, the cancer is relapsed or refractory angiosarcoma. In one embodiment, the cancer is relapsed or refractory ROS1+ angiosarcoma. In one embodiment, the cancer is relapsed or refractory ALK+ angiosarcoma. In one embodiment, the cancer is a newly diagnosed angiosarcoma. In one embodiment, the cancer is a newly diagnosed ROS1+ angiosarcoma. In one embodiment, the cancer is a newly diagnosed ALK+ angiosarcoma.

[0368] In one embodiment, the cancer is melanoma. In one embodiment, the cancer is a Spitz nevus-like tumor. In one embodiment, the cancer is a Spitz nevus-like melanoma. In one embodiment, the cancer is ROS1+ Spitz nevus-like melanoma. In one embodiment, the cancer is ALK+ Spitz nevus-like melanoma. In one embodiment, the cancer is relapsed or refractory Spitz nevus-like melanoma. In one embodiment, the cancer is relapsed or refractory ROS1+ Spitz nevus-like melanoma. In one embodiment, the cancer is relapsed or refractory ALK+ Spitz nevus-like melanoma. In one embodiment, the cancer is a newly diagnosed Spitz nevus-like melanoma. In one embodiment, the cancer is a newly diagnosed ROS1+ Spitz nevus-like melanoma. In one embodiment, the cancer is a newly diagnosed ALK+ Spitz nevus-like melanoma.

[0369] In one embodiment, the cancer is an epithelioid hemangioendothelioma. In one embodiment, the cancer is a ROS1+ epithelioid hemangioendothelioma. In one embodiment, the cancer is an ALK+ epithelioid hemangioendothelioma. In one embodiment, the cancer is a relapsed or refractory epithelioid hemangioendothelioma. In one embodiment, the cancer is a relapsed or refractory ROS1+ epithelioid hemangioendothelioma. In one embodiment, the cancer is a relapsed or refractory ALK+ epithelioid hemangioendothelioma. In one embodiment, the cancer is a newly diagnosed epithelioid hemangioendothelioma. In one embodiment, the cancer is a newly diagnosed ROS1+ epithelioid hemangioendothelioma. In one embodiment, the cancer is a newly diagnosed ALK+ epithelioid hemangioendothelioma.

[0370] In one embodiment, the cancer is esophageal cancer. In one embodiment, the cancer is ESCC. In one embodiment, the cancer is ROS1+ESCC. In one embodiment, the cancer is ALK+ESCC. In one embodiment, the cancer is relapsed or refractory ESCC. In one embodiment, the cancer is relapsed or refractory ROS1+ESCC. In one embodiment, the cancer is relapsed or refractory ALK+ESCC. In one embodiment, the cancer is newly diagnosed ESCC. In one embodiment, the cancer is newly diagnosed ROS1+ESCC. In one embodiment, the cancer is newly diagnosed ALK+ESCC.

[0371] In one embodiment, the cancer is renal cell carcinoma. In one embodiment, the cancer is renal medullary carcinoma. In one embodiment, the cancer is ROS1+ renal medullary carcinoma. In one embodiment, the cancer is ALK+ renal medullary carcinoma. In one embodiment, the cancer is relapsed or refractory renal medullary carcinoma. In one embodiment, the cancer is relapsed or refractory ROS1+ renal medullary carcinoma. In one embodiment, the cancer is relapsed or refractory ALK+ renal medullary carcinoma. In one embodiment, the cancer is newly diagnosed renal medullary carcinoma. In one embodiment, the cancer is newly diagnosed ROS1+ renal medullary carcinoma. In one embodiment, the cancer is newly diagnosed ALK+ renal medullary carcinoma. In one embodiment, the cancer is renal cell carcinoma. In one embodiment, the cancer is ROS1+ renal cell carcinoma. In one embodiment, the cancer is ALK+ renal cell carcinoma. In one embodiment, the cancer is relapsed or refractory renal cell carcinoma. In one embodiment, the cancer is relapsed or refractory ROS1+ renal cell carcinoma. In one embodiment, the cancer is relapsed or refractory ALK+ renal cell carcinoma. In one embodiment, the cancer is newly diagnosed renal cell carcinoma. In one implementation, the cancer is a newly diagnosed ROS1+ renal cell carcinoma. In another implementation, the cancer is a newly diagnosed ALK+ renal cell carcinoma.

[0372] In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is ROS1+ breast cancer. In one embodiment, the cancer is ALK+ breast cancer. In one embodiment, the cancer is recurrent or refractory breast cancer. In one embodiment, the cancer is recurrent or refractory ROS1+ breast cancer. In one embodiment, the cancer is recurrent or refractory ALK+ breast cancer. In one embodiment, the cancer is newly diagnosed breast cancer. In one embodiment, the cancer is newly diagnosed ROS1+ breast cancer. In one embodiment, the cancer is newly diagnosed ALK+ breast cancer. In one embodiment, the breast cancer is triple-negative breast cancer.

[0373] In one embodiment, the cancer is colon cancer. In one embodiment, the cancer is ROS1+ colon cancer. In one embodiment, the cancer is ALK+ colon cancer. In one embodiment, the cancer is recurrent or refractory colon cancer. In one embodiment, the cancer is recurrent or refractory ROS1+ colon cancer. In one embodiment, the cancer is recurrent or refractory ALK+ colon cancer. In one embodiment, the cancer is newly diagnosed colon cancer. In one embodiment, the cancer is newly diagnosed ROS1+ colon cancer. In one embodiment, the cancer is newly diagnosed ALK+ colon cancer.

[0374] In one embodiment, the cancer is thyroid cancer. In one embodiment, the cancer is papillary thyroid carcinoma. In one embodiment, the cancer is ROS1+ papillary thyroid carcinoma. In one embodiment, the cancer is ALK+ papillary thyroid carcinoma. In one embodiment, the cancer is recurrent or refractory papillary thyroid carcinoma. In one embodiment, the cancer is recurrent or refractory ROS1+ papillary thyroid carcinoma. In one embodiment, the cancer is recurrent or refractory ALK+ papillary thyroid carcinoma. In one embodiment, the cancer is newly diagnosed papillary thyroid carcinoma. In one embodiment, the cancer is newly diagnosed ROS1+ papillary thyroid carcinoma. In one embodiment, the cancer is newly diagnosed ALK+ papillary thyroid carcinoma.

[0375] In one embodiment, the cancer is a neuroblastoma. In one embodiment, the cancer is a ROS1+ neuroblastoma. In one embodiment, the cancer is an ALK+ neuroblastoma. In one embodiment, the cancer is a relapsed or refractory neuroblastoma. In one embodiment, the cancer is a relapsed or refractory ROS1+ neuroblastoma. In one embodiment, the cancer is a relapsed or refractory ALK+ neuroblastoma. In one embodiment, the cancer is a newly diagnosed neuroblastoma. In one embodiment, the cancer is a newly diagnosed ROS1+ neuroblastoma. In one embodiment, the cancer is a newly diagnosed ALK+ neuroblastoma.

[0376] In one implementation, the cancer (or ROS1+ cancer or ALK+ cancer) is a blood cancer. In one implementation, the cancer (or ROS1+ cancer or ALK+ cancer) is a lymphoma. In one implementation, the lymphoma is non-Hodgkin's lymphoma. In one implementation, the lymphoma is anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), or large B-cell lymphoma. In addition to blood cancers, this document also provides methods for treating other blood disorders or blood malignancies that are ROS1+ or ALK+.

[0377] In one embodiment, the cancer is ALCL. In one embodiment, the cancer is ROS1+ALCL. In one embodiment, the cancer is ALK+ALCL. In one embodiment, the cancer is relapsed or refractory ALCL. In one embodiment, the cancer is relapsed or refractory ROS1+ALCL. In one embodiment, the cancer is relapsed or refractory ALK+ALCL. In one embodiment, the cancer is newly diagnosed ALCL. In one embodiment, the cancer is newly diagnosed ROS1+ALCL. In one embodiment, the cancer is newly diagnosed ALK+ALCL.

[0378] In one embodiment, the cancer is DLBCL. In one embodiment, the cancer is ROS1+DLBCL. In one embodiment, the cancer is ALK+DLBCL. In one embodiment, the cancer is relapsed or refractory DLBCL. In one embodiment, the cancer is relapsed or refractory ROS1+DLBCL. In one embodiment, the cancer is relapsed or refractory ALK+DLBCL. In one embodiment, the cancer is newly diagnosed DLBCL. In one embodiment, the cancer is newly diagnosed ROS1+DLBCL. In one embodiment, the cancer is newly diagnosed ALK+DLBCL.

[0379] In one embodiment, the cancer is large B-cell lymphoma. In one embodiment, the cancer is ROS1+ large B-cell lymphoma. In one embodiment, the cancer is ALK+ large B-cell lymphoma. In one embodiment, the cancer is relapsed or refractory large B-cell lymphoma. In one embodiment, the cancer is relapsed or refractory ROS1+ large B-cell lymphoma. In one embodiment, the cancer is relapsed or refractory ALK+ large B-cell lymphoma. In one embodiment, the cancer is newly diagnosed large B-cell lymphoma. In one embodiment, the cancer is newly diagnosed ROS1+ large B-cell lymphoma. In one embodiment, the cancer is newly diagnosed ALK+ large B-cell lymphoma.

[0380] In one implementation, the cancer (or ROS1+ cancer or ALK+ cancer) is newly diagnosed. In another implementation, the cancer (or ROS1+ cancer or ALK+ cancer) has not been previously treated.

[0381] In one implementation, the cancer (or ROS1+ cancer or ALK+ cancer) is relapsed or refractory. In one implementation, the cancer is relapsed. In one implementation, the cancer (or ROS1+ cancer or ALK+ cancer) is refractory.

[0382] In one embodiment, the subject has not received prior treatment. In one embodiment, the subject has not been treated with a tyrosine kinase inhibitor (TKI) therapy. In one embodiment, the subject has received one or more prior therapies. In one embodiment, the subject has received two or more prior therapies. In one embodiment, the subject has developed resistance to one or more prior therapies. In one embodiment, the prior therapy includes a tyrosine kinase inhibitor (TKI). In one embodiment, the prior therapy includes one or more of crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, loprotinib, cabozantinib, foretinib, taletrectinib, merestinib, masitinib, and ensartinib. In one embodiment, the prior therapy includes one or more chemotherapy therapies. In one embodiment, one or more chemotherapy therapies are supplemental to TKI therapy.

[0383] In one implementation, the cancer (or ROS1+ cancer or ALK+ cancer) is resistant to tyrosine kinase inhibitors (TKIs).

[0384] In one embodiment, the cancer is drug-resistant lung cancer. In one embodiment, the cancer is drug-resistant non-small cell lung cancer. In one embodiment, the cancer is non-small cell lung cancer resistant to TKI. In one embodiment, the cancer is ROS1+ non-small cell lung cancer resistant to TKI. In one embodiment, the cancer is ALK+ non-small cell lung cancer resistant to TKI.

[0385] In one implementation, the cancer is lung cancer (e.g., NSCLC), and the cancer has relapsed after treatment with a TKI or was refractory before the treatment.

[0386] In one embodiment, the compound provided herein is administered as first-line treatment. In one embodiment, the compound provided herein is administered as second-line treatment. In one embodiment, the compound provided herein is administered as third- or fourth-line treatment.

[0387] In one embodiment, the cancer (or ROS1+ cancer or ALK+ cancer) is metastatic. In one embodiment, the cancer has CNS metastases. In one embodiment, the cancer has brain metastases. In one embodiment, the cancer is metastatic non-small cell lung cancer (NSCLC). In one embodiment, the cancer is metastatic ROS1+ NSCLC. In one embodiment, the cancer is metastatic ALK+ NSCLC.

[0388] In one embodiment, this document provides a method for treating a patient with metastatic ALK+ non-small cell lung cancer (NSCLC), comprising administering to the patient a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0389] In one embodiment, this document provides a method for treating a patient with metastatic ROS1+ non-small cell lung cancer (NSCLC), comprising administering to the patient a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0390] In one implementation, the patient is an adult patient. In another implementation, the patient is a pediatric patient.

[0391] In one embodiment, this document provides a method for treating an adult patient with metastatic ROS1+ NSCLC, comprising administering to the patient a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0392] In one embodiment, this document provides a method for treating an adult patient with metastatic ROS1+ NSCLC, comprising administering to the patient a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the patient has progressed or is intolerant to at least one prior TKI therapy.

[0393] In one embodiment, this document provides a method for treating an adult patient with metastatic NSCLC that is ROS1+ and has a solvent-front mutation G2032R, the method comprising administering to the patient a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the patient has progressed or is intolerant to at least one prior TKI therapy.

[0394] In one embodiment, this document provides a method for treating a subject with ROS1-related (or ROS1+) cancer that has developed resistance to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0395] In one embodiment, this document provides a method for treating ROS1-related (or ROS1+) cancer in a subject of need, wherein the cancer is resistant to a tyrosine kinase inhibitor (TKI), and wherein the cancer has been identified as having one or more ROS1 inhibitor resistance mutations. The method comprises administering to the subject a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise one or more amino acid substitutions selected from the amino acid positions of 1986, 2004, 2026, 2032, and 2033. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise one or more amino acid substitutions selected from S1986F, S1986Y, F2004C, F2004V, L2026M, G2032R, D2033N, L2086F, and G2101A. In one embodiment, one or more ROS1 inhibitor resistance mutations are G2032R. In one embodiment, one or more ROS1 inhibitor resistance mutations include G2032R and one or more of S1986F, S1986Y, F2004C, F2004V, L2026M, D2033N, or G2101A. In one embodiment, the ROS1 inhibitor resistance mutation is L2086F.

[0396] In one embodiment, this document provides a method for treating ALK-related (or ALK+) cancer in a subject of need, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0397] In one embodiment, this document provides a method for treating ALK-related (or ALK+) cancer in a subject of need, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), and wherein the cancer has been identified as having one or more ALK inhibitor resistance mutations. The method comprises administering to the subject a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the one or more ALK inhibitor resistance mutations comprise one or more amino acid substitutions at positions selected from amino acids 1196, 1198, 1202, and 1269. In one embodiment, the one or more ALK inhibitor resistance mutations comprise one or more amino acid substitutions selected from L1196M, L1198F, G1202R, and G1269A. In one embodiment, the one or more ALK inhibitor resistance mutations are G1202R. In one implementation, one or more ALK inhibitor resistance mutations include one or more of G1202R and L1196M, L1198F, and G1269A.

[0398] In one embodiment, this document provides a method for treating an adult patient with metastatic NSCLC, the metastatic NSCLC being ALK+ with the G1202R mutation, the method comprising administering to the patient a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the patient has progressed or is intolerant to at least one prior TKI therapy.

[0399] In one embodiment, this document provides a method for treating ALK-related (or ALK+) cancer in a subject of need, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, mixture of enantiomers, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0400] In one embodiment, the TKI is a ROS1 inhibitor. In one embodiment, the TKI is an ALK inhibitor. In one embodiment, the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, loprotinib, cabozantinib, faritinib, mesatinib, talectinib, masitinib, or ensartinib. In one embodiment, the TKI is crizotinib. In one embodiment, the TKI is entrectinib.

[0401] In some implementations, the subject experienced cancer recurrence after first-line cancer treatment. In other implementations, the subject experienced cancer recurrence after second-line cancer treatment.

[0402] In one implementation, the cancer or disease occurs in a pediatric patient (including an infant). In one implementation, the cancer in pediatric patients aged 1 year or older and young adults is ALK+ systemic anaplastic large cell lymphoma (ALCL). In another implementation, the cancer in pediatric patients aged 1 year or older and young adults is ALK+ relapsed or refractory systemic anaplastic large cell lymphoma (ALCL). In one implementation, the cancer in pediatric patients aged 1 year or older and young adults is ROS1+ systemic anaplastic large cell lymphoma (ALCL). In another implementation, the cancer in pediatric patients aged 1 year or older and young adults is ROS1+ relapsed or refractory systemic anaplastic large cell lymphoma (ALCL).

[0403] In some implementations, the method for treating or preventing cancer can be demonstrated through one or more reactions, such as increased apoptosis, inhibition of tumor growth, reduction of tumor metastasis, inhibition of tumor metastasis, reduction of microvascular density, reduction of neovascularization, inhibition of tumor migration, tumor regression, and increased subject survival.

[0404] Combination therapy

[0405] In some implementations, methods of treating or preventing cancer may include the combined administration of a compound of formula (I) and one or more other chemotherapeutic agents.

[0406] As used herein, unless otherwise stated, “combination” or “aggregation” does not mean that other agents and compounds of formula (I) must be administered simultaneously and / or formulated for delivery together, although such delivery methods are also within the scope of this invention. The compounds provided herein may be administered simultaneously with, before (e.g., before 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks) or after (e.g., after 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks). Generally, each therapeutic agent is administered at a dose and / or schedule determined for the specific drug. Other therapeutic agents may be administered in a single composition with the compounds provided herein or alone in different compositions. Triple therapy is also considered herein.

[0407] Chemotherapy agents that can be used in combination with the compounds disclosed herein include: 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (Acid Blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-Amino-4-[1-Naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-Amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-Amino-4-[2-anthraylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, ABT-263, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette-Guérin (BCG) Calmette-Guérinvaccine (bcg), bicalutamide, bleomycin, bortezomib, β-methylene-ADP (AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, camptothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine Chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone, vidarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxelDoxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide Gefitinib, Gemcitabine, Genistein, Goserelin, GSK1120212, Hydroxyurea, Idarubicin, Ifosfamide, Imatinib, Interferon, Irinotecan, Ixabepilone, Lenalidomide, Letrozole, Leucovorin, Leuprolide, Levamisole, Lomustyl Lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, mutamycin, N -(4-aminosulfonylphenylaminomethylthio)palmitamide, NF279, NF449, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemexetred, pentostatin, perifosine, PF-04691502, plicamycinPomalidomide, porfimer, PPADS, procarbazine, quercetin, raltitrexed, ramucirumab, Active Blue 2, rituximab, rolofylline, romidepsin, rucaparib, selumetinib, sirolimus, sodium 2,4-dinitrobenzenesulfonate, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen The compounds include amoxifen, temozolomide, sirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, dichlorodicyclopentazone, tonapofylline, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, vinorelbine, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that can be administered in combination with the compounds disclosed herein include ABT-263, dexamethasone, 5-fluorouracil, PF-04691502, romidesin, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that can be administered in combination with the compounds of this disclosure include: 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (Acid Blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-Amino-4-[2-anthraylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, APCP, β-methylene-ADP (AOPCP), capecitabine, cladribine, arachidonic acid, fludarabine, doxorubicin, gemcitabine, N-(4-aminosulfonylphenylaminomethylthio)palmitamide, NF279, NF449, PPADS, quercetin, Reactive Blue 2, rolofeline, sodium 2,4-dinitrobenzenesulfonate, sumarin, and tanpheneline.

[0408] Numerous combination therapies for treating cancer have been developed. In some embodiments, the compounds of this disclosure (e.g., compounds of formula (I)) can be administered in combination with one or more combination therapies. Table 2 includes examples of combination therapies that can be administered in combination with the compounds of this disclosure.

[0409] Table 2: Exemplary combination therapies for treating cancer

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416] In some embodiments, the combination therapies of this disclosure include combined administration with other types of chemotherapy agents, such as immuno-oncology agents. Cancer cells typically possess specific cell surface antigens that can be recognized by the immune system. Therefore, immuno-oncology agents such as monoclonal antibodies can selectively bind to cancer cell antigens and induce cell death. Other immuno-oncology agents can suppress tumor-mediated inhibition of the innate immune response or activate the immune response, thereby promoting the immune system's recognition of the tumor. Exemplary antibody immuno-oncology agents include, but are not limited to, abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, and inotuzumab. The antibody immuno-oncology agents are selected from anti-CD73 monoclonal antibodies (mAbs), anti-CD39 mAbs, anti-PD-1 mAbs, and anti-CTLA4 mAbs. Other options include ozogamicin, intelumumab, ipilimumab, isatuximab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, and tremelimumab. In some embodiments, the antibody immuno-oncology agent is selected from anti-CD73 monoclonal antibodies (mAbs), anti-CD39 mAbs, anti-PD-1 mAbs, and anti-CTLA4 mAbs. Therefore, in some embodiments, the method disclosed herein includes the combined administration of one or more immunotumor agents, such as the agents described above.

[0417] In some embodiments, the combination therapy includes the combined administration of a compound of the present disclosure (e.g., compound of formula (I)) with an SH2 inhibitor (e.g., CGP78850, CPG85793, C90, C126, G7-18NATE, G7-B1 and NSC642056).

[0418] In some implementations, combination therapy includes the combined administration of a compound disclosed herein (e.g., compound of formula (I)) with a MEK inhibitor (e.g., trametinib, cobimetinib, binimetinib, selumetinib, PD-325901, CI-1040, and TAK-733).

[0419] In some embodiments, the combination therapy comprises the combined administration of a compound of the present disclosure (e.g., a compound of formula (I)) with a MET inhibitor selected from JNJ-38877605, PF-04217903, furitinib, AMG458, tivantinib, cabozantinib, crizotinib, capmatinib hydrochloride, tepotinib hydrochloride, and savolitinib.

[0420] In some embodiments, the combination therapy includes the combined administration of a compound of the present disclosure (e.g., compound of formula (I)) with an SHP2 inhibitor selected from TNO-155, RMC-4630, JAB-3068 or RLY-1971.

[0421] In some implementations, the combination therapy includes the combined administration of a compound of the present disclosure (e.g., a compound of formula (I)) with a RAS inhibitor selected from: aliskiren, captopril, losartan, irbesartan, olmesartan, candesartan, valsartan, fimasartan, azilsartan, telmisartan, eprosartan, benazepril, enalapril, lisinopril, perindopril, quinapril, ramipril, and trandolapril.

[0422] In some embodiments, the combination therapy comprises administration of a compound provided herein (e.g., compound of formula (I)) in combination with a TKI. In one embodiment, the TKI is a ROS1 inhibitor. In one embodiment, the TKI is an ALK inhibitor. In one embodiment, the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, loprotinib, cabozantinib, faritinib, mesatinib, talectinib, masatinib, or ensartinib. In one embodiment, the TKI is crizotinib. In one embodiment, the TKI is entrectinib. In one embodiment, the TKI is alectinib. In one embodiment, the TKI is brigatinib.

[0423] In some embodiments, the combination therapy comprises the combined administration of a compound of the present disclosure (e.g., compound of formula (I)) and anti-PD-1 therapy. In some embodiments, the combination therapy comprises the combined administration of a compound of the present disclosure (e.g., compound of formula (I)) and oxaliplatin. In other embodiments, the combination therapy comprises the combined administration of a compound of the present disclosure (e.g., compound of formula (I)) and doxorubicin.

[0424] In some embodiments, the compounds of this disclosure may be administered in combination with non-chemical methods of cancer treatment. In some embodiments, the compounds of this disclosure may be administered in combination with radiotherapy. In some embodiments, the compounds of this disclosure may be administered in combination with surgery, thermal ablation, ultrasound-guided focused therapy, cryotherapy, or any combination of these therapies.

[0425] In some embodiments, the compounds of this disclosure may be administered in combination with one or more other compounds of this disclosure. Furthermore, such combinations may be administered in combination with other therapeutic agents, such as other drugs suitable for treating cancer, immune, or neurological disorders, such as those identified above. In some embodiments, the combined administration of one or more additional chemotherapy agents provides a synergistic effect with the compounds of this disclosure. In some embodiments, the combined administration of one or more additional chemotherapy agents provides an additive effect.

[0426] Pharmaceutical Composition

[0427] In some embodiments, this disclosure provides pharmaceutical formulations suitable for human patients, comprising any of the compounds shown above (e.g., compounds of this disclosure, such as compounds of formula (I)) and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical formulations may be used to treat or prevent the diseases or ailments described herein. Any disclosed compound may be used to prepare a medicament for treating any of the diseases or ailments disclosed herein.

[0428] The compositions and methods disclosed herein can be used to treat subjects in need. In some embodiments, the subject is a mammal, such as a human or a non-human mammal. When administered to a subject, such as a human, the composition or compound is preferably administered as a pharmaceutical composition comprising, for example, a compound disclosed herein and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions (such as water or physiologically buffered saline) or other solvents or media (such as ethylene glycol, glycerin, oils (such as olive oil), or injectable organic esters). In a preferred embodiment, when such pharmaceutical compositions are used for human administration, particularly for invasive routes of administration (i.e., routes such as injection or implantation that avoid transport or diffusion across the epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients may be selected, for example, to achieve delayed release of the agent or selective targeting of one or more cells, tissues, or organs. The pharmaceutical composition may be in the form of dosage units, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized formulations for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition may also be present in transdermal delivery systems, such as skin patches. The composition may also be present in solutions suitable for topical application, such as eye drops.

[0429] Pharmaceutically acceptable carriers may contain physiologically acceptable agents that, for example, stabilize compounds such as those disclosed herein, increase their solubility, or enhance their absorption. Such physiologically acceptable agents include, for example, carbohydrates (such as glucose, sucrose, or dextran), antioxidants (such as ascorbic acid or glutathione), chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of pharmaceutically acceptable carriers (including physiologically acceptable agents) depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may also be a liposome or other polymer matrix in which compounds such as those disclosed herein may be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers, and their preparation and administration are relatively simple.

[0430] The phrase “pharmaceutically acceptable” in this document means those compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of a subject, within the limits of reasonable medical judgment, without excessive toxicity, irritation, allergic reactions, or other problems or complications, and in proportion to a reasonable benefit / risk ratio.

[0431] As used herein, the phrase “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is harmless to the subject. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, and corn oil. (10) Soybean oil; (11) Diols, such as propylene glycol; (12) Polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (13) Esters, such as ethyl oleate and ethyl laurate; (14) Agar; (15) Buffers, such as magnesium hydroxide and aluminum hydroxide; (16) Alginate; (17) Pyrogen-free water; (18) Isotonic saline; (19) Ringer's solution; (10) Ethanol; (21) Phosphate buffer solution; and (22) Other non-toxic and compatible substances used in pharmaceutical preparations.

[0432] The pharmaceutical composition (formulation) can be administered to a subject via any of a variety of routes of administration, including, for example, oral (e.g., as an infusion or suspension in the form of an aqueous or non-aqueous solution, tablets, capsules (including sprinkle capsules and gelatin capsules), pills, powders, granules, or pastes applied to the tongue); absorption through the oral mucosa (e.g., sublingual); anal, rectal, or vaginal (e.g., as a vaginal suppository, cream, or foam); parenteral (including intramuscular, intravenous, subcutaneous, or intrathecal, e.g., as a sterile solution or suspension); nasal; intraperitoneal; subcutaneous; percutaneous (e.g., as a patch applied to the skin); and topical (e.g., as a cream, ointment, or spray applied to the skin, or as eye drops). The compound can also be formulated for inhalation. In some embodiments, the compound can simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable for said routes can be found, for example, in the following U.S. Patent Nos.: 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896 and the patents referenced therein.

[0433] The formulation can be conveniently present in a unit dosage form and can be prepared by any method well known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated and the specific route of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound that produces the therapeutic effect. Typically, in 100%, this amount will range from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%.

[0434] Methods for preparing these formulations or compositions include the step of combining an active compound, such as a compound disclosed herein, with a carrier and optionally one or more auxiliary components. Typically, formulations are prepared by homogenizing and tightly binding a compound disclosed herein with a liquid carrier or a finely fragmented solid carrier, or both, and then shaping the product as needed.

[0435] Formulations of this disclosure suitable for oral administration may be in the form of capsules (including sprinkled capsules and gelatin capsules), flat capsules, pills, tablets, lozenges (using a flavoring matrix, typically sucrose and gum arabic or tragacanth), lyophilized formulations, powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as confectionery lozenges (using an inert matrix (e.g., gelatin and glycerin) or sucrose and gum arabic) and / or as mouthwashes, etc., each form containing a predetermined amount of the compound of this disclosure as an active ingredient. The composition or compound may also be administered in the form of pills, granules, or pastes.

[0436] To prepare solid dosage forms (capsules (including spread gels and gelatin gels), tablets, pills, sugar tablets, powders, granules, etc.) for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers (such as sodium citrate or dicalcium phosphate) and / or any of the following: (1) fillers or enriching agents, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, etc. Examples of active ingredients include: (4) disintegrants such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates, and sodium carbonate; (5) solution delay agents such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as, for example, cetyl alcohol and glyceryl monostearate; (8) absorbents such as kaolin and bentonite; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents such as modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including spread capsules and gelatin capsules), tablets, and pills, the pharmaceutical composition may also contain a buffer. Similar types of solid compositions may also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycol.

[0437] Tablets can optionally be prepared by compression or molding with one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0438] The tablets and other solid dosage forms of the pharmaceutical compositions, such as sugar-coated pills, capsules (including sprinkled capsules and gelatin capsules), pellets, and granules, can optionally be scored or prepared using coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation field. They can also be formulated using, for example, different proportions of hydroxypropyl methylcellulose, other polymer matrices, liposomes, and / or microspheres that provide the desired release profile to provide a slow or controlled release of the active ingredient therein. They can be sterilized by filtration, for example, using a bacterial trap filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that dissolves immediately in sterile water or some other sterile injection medium before use. These compositions may also optionally contain an opacifying agent and can be compositions that optionally release the active ingredient in a delayed manner only or preferably in a specific portion of the gastrointestinal tract. Examples of encapsulation compositions that can be used include polymeric substances and waxes. If suitable, the active ingredient may also be in a microencapsulated form with one or more of the excipients described above.

[0439] Liquid dosage forms suitable for oral administration include pharmaceutically acceptable emulsions, lyophilized formulations for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and their derivatives, solubilizers, and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuranol, polyethylene glycol, and fatty acid esters and mixtures thereof of sorbitol.

[0440] In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, aroma agents, and preservatives.

[0441] In addition to the active ingredient, suspensions may also contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and astragalus gum, and mixtures thereof.

[0442] Pharmaceutical compositions for rectal, vaginal, or urethral administration can be in the form of suppositories, which can be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylates, and are solid at room temperature but liquid at body temperature, thus melting and releasing the active compound in the rectal or vaginal cavity.

[0443] Formulations of pharmaceutical compositions for oral application may be in the form of mouthwash, oral spray, or oral ointment.

[0444] Alternatively or additionally, the composition can be formulated for delivery via catheters, stents, lines or other endoluminal devices. Delivery via such devices is particularly suitable for delivery to the bladder, urethra, ureter, rectum or intestine.

[0445] Preparations suitable for vaginal application also include vaginal suppositories, tampons, creams, gels, pastes, foams or sprays containing suitable carriers known in the art.

[0446] Dosage forms for topical or transdermal application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active compound can be mixed under aseptic conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants that may be necessary.

[0447] In addition to the active compound, the ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, astragalus gum, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0448] In addition to the active compound, powders and aerosols may contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Aerosols may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane or propane).

[0449] Transdermal patches offer the added advantage of controlled delivery of the compounds disclosed herein to the body. Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers can also be used to increase the flow rate of the compound across the skin. The rate of this flow can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0450] Ophthalmic preparations, ophthalmic ointments, powders, solutions, etc., are also considered to be within the scope of this disclosure. Exemplary ophthalmic preparations are described in U.S. Publications 2005 / 0080056, 2005 / 0059744, 2005 / 0031697, and 2005 / 004074, and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference. Liquid ophthalmic preparations may, when desired, have properties similar to, or be compatible with, tears, aqueous humor, or vitreous fluid. Preferred routes of administration are topical application (e.g., topical application, such as eye drops, or application via an implant).

[0451] As used herein, the phrase “parenteral administration and administered parenterally” refers to administration other than enteral and local administration (usually by injection), and does not include, but is not limited to, intravenous, intramuscular, intra-arterial, intrasheath, intracapsular, intra-sacral, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, spinal, and intrasternal injections and infusions.

[0452] Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds and one or more pharmaceutically acceptable sterile isotonic or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions prior to use. The latter may contain antioxidants, buffers, antibacterial agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0453] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions disclosed herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Appropriate flowability can be maintained, for example, by using a coating material (such as lecithin), in the case of a dispersion by maintaining the desired particle size, and by using a surfactant.

[0454] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It is also desirable to include isotonic agents in the composition, such as sugars, sodium chloride, etc. Furthermore, prolonged absorption of injectable drug forms can be achieved by including delayed absorption agents such as aluminum monostearate and gelatin.

[0455] In some cases, to prolong the effect of a drug, it is necessary to slow its absorption from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous substance. The absorption rate of the drug depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of parenteral drug forms can be achieved by dissolving or suspending the drug in an oil-based medium.

[0456] Injectable reservoir formulations are prepared by forming a microcapsule matrix of the subject compound in a biodegradable polymer such as poly(lactide-polyglycolic acid). The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Reservoir-type injectable formulations are also prepared by encapsulating the drug in tissue-compatible liposomes or microemulsions.

[0457] For use in the methods disclosed herein, the active compound may be administered either alone or as a pharmaceutical composition comprising, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0458] The introduced methods can also be provided by rechargeable or biodegradable devices. In recent years, various sustained-release polymer devices have been developed and tested in vivo for the controlled delivery of drugs, including protein biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), both biodegradable and non-degradable, can be used to form implants that sustainably release compounds at specific target sites.

[0459] The actual dose level of the active ingredient in a pharmaceutical composition can be varied in order to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and method of administration and is non-toxic to the patient.

[0460] The selected dose level will depend on a variety of factors, including the activity of the specific compound or combination of compounds or its esters, salts or amides, the route of administration, the time of administration, the excretion rate of the specific compound, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific compound, the age, sex, weight, disease, general health and medical history of the subject being treated, and similar factors well known in the medical field.

[0461] A physician or veterinarian with ordinary skills in the art can readily determine and prescribe a therapeutically effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian may start with a dose of the pharmaceutical composition or compound at a level lower than the desired level to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. “Therapeutically effective amount” means the concentration of the compound sufficient to cause the desired therapeutic effect. It is generally believed that the effective amount of a compound will vary depending on the subject’s weight, sex, age, and medical history. Other factors affecting the effective amount may include, but are not limited to, the severity of the subject’s illness, the disease being treated, the stability of the compound, and another type of therapeutic agent administered with the compound of this disclosure when necessary. A larger total dose may be delivered by administering the pharmaceutical agent multiple times. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine, 13th edition, 1814-1882, which is incorporated herein by reference).

[0462] Generally, the appropriate daily dose of the active compound used in the compositions and methods of this disclosure will be the minimum amount of compound that effectively produces a therapeutic effect. This effective dose generally depends on the factors mentioned above.

[0463] If desired, the effective daily dose of the active compound may be administered at appropriate intervals throughout the day in one, two, three, four, five, six, or more fractions, optionally alone in a single dosage form. In some embodiments of this disclosure, the active compound may be administered two or three times daily. In some embodiments, the active compound will be administered once daily.

[0464] In some embodiments, the compounds of this disclosure may be used alone or in combination with another type of therapeutic agent. As used herein, the phrase "combined administration" refers to any form of administration of two or more different therapeutic compounds such that the previously administered therapeutic compound remains effective in the body while the second compound is being administered (e.g., both compounds are effective simultaneously in the subject, which may include a synergistic effect between the two compounds). For example, different therapeutic compounds may be administered simultaneously or sequentially in the same formulation or in separate formulations. In some embodiments, different therapeutic compounds may be administered over 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or one week. Thus, a subject receiving such treatment may benefit from the combined effect of the different therapeutic compounds.

[0465] In some embodiments, combined administration of the disclosed compound with one or more other therapeutic agents (e.g., one or more other chemotherapeutic agents) provides improved efficacy relative to each individual administration of the disclosed compound (e.g., compound of formula I or Ia) or one or more other therapeutic agents. In some such embodiments, combined administration provides an additive effect, wherein the additive effect refers to the sum of the effects of each of the disclosed compound and one or more other therapeutic agents administered individually.

[0466] This disclosure includes the use of pharmaceutically acceptable salts of the compounds of this disclosure in the compositions and methods of this disclosure. In some embodiments, the intended salts of this disclosure include, but are not limited to, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, or tetraalkylammonium salts. In some embodiments, the intended salts of this disclosure include, but are not limited to, L-arginine salts, benzylbenzylamine salts, benzathine penicillin salts, betaine salts, calcium hydroxide, choline salts, deanol salts, diethanolamine salts, diethylamine salts, 2-(diethylamino)ethanol salts, ethanolamine salts, ethylenediamine salts, N-methylglucosamine salts, hydrabamine salts, 1H-imidazolium salts, lithium salts, L-lysine salts, magnesium salts, 4-(2-hydroxyethyl)morpholine salts, piperazine salts, potassium salts, 1-(2-hydroxyethyl)pyrrolidine salts, sodium salts, triethanolamine salts, tromethamine salts, and zinc salts. In some embodiments, the intended salts of this disclosure include, but are not limited to, Na salts, Ca salts, K salts, Mg salts, Zn salts, or other metal salts.

[0467] Pharmaceutically acceptable acid addition salts can also exist in various solvate forms, such as solvates with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates can also be prepared. These solvates can originate from the solvent used for crystallization, be inherent to the solvent used for preparation or crystallization, or be incidental to such solvents.

[0468] Pharmaceutically acceptable anionic salts include acetates, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, tartrate, bromide, camphor sulfonate, carbonate, chloride, citrate, decanoate, ethylenediaminetetraacetate, ethanesulfonate, fumarate, gluconate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthyl salt, iodide, hydroxyethanesulfonate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, methyl sulfate, mucilage, naphthalenesulfonate, nitrate, caprylate, oleate, dihydroxynaphthyl salt, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate, sulfate, tartrate, theophylline, and toluenesulfonate.

[0469] Wetting agents, emulsifiers and lubricants, such as sodium dodecyl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavorings and aromas, preservatives and antioxidants may also be present in the composition.

[0470] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0471] This disclosure will now be described in general terms, and will be more readily understood by referring to the following embodiments, which are included only for the purpose of illustrating certain aspects and implementations of this disclosure and are not intended to limit this disclosure.

[0472] General synthesis procedure

[0473] The raw materials and reagents used to prepare these compounds can be obtained from commercial suppliers such as Aldrich Chemical Co., Bachem, etc., or can be prepared by methods known in the art. These schemes are merely illustrative of some methods by which the compounds disclosed herein can be synthesized, and various modifications can be made to these schemes, which will be proposed by those skilled in the art with reference to this disclosure. If necessary, the starting materials, intermediates, and final products of the reaction can be separated and purified using conventional techniques (including, but not limited to, filtration, distillation, crystallization, chromatography, etc.), and can be characterized using conventional means (including physical constants and spectroscopic data). In some cases, the reaction may produce more than one regiomeric product. In these cases, chromatography can be used to separate the isomers, and NOE or NOESY NMR spectroscopy can be used to assist in structural identification.

[0474] Unless otherwise stated, the reactions described herein are carried out at atmospheric pressure in a temperature range of about -78°C to about 150°C.

[0475]

[0476]

[0477] The compounds of this invention can be prepared by a variety of synthetic methods, as further described and illustrated herein. Those skilled in the art will understand that the following general synthetic methods are representative and not limiting. Racemic compounds can be enriched for enantiomers by chiral, preparative, SFC, or HPLC separation. Variable A represents a carbon, nitrogen, or sulfur atom that may be the same as or different from another instance of variable A. Variable X represents a chlorine, bromine, or iodine atom that may be the same as or different from another instance of variable X. Variable Z represents a nitrogen atom or a CH or CF group that may be the same as or different from another instance of variable Z.

[0478] Method A

[0479]

[0480] Polyhalides I can be coupled with tinane II under Stille coupling conditions to provide type III compounds. Various additives, including (but not limited to) LiCl or CuI, can optionally be used to promote the reaction. Intramolecular ring closure of polyhalides III can be achieved using a two-step one-pot borylation / Suzuki cross-coupling process to provide type IV compounds.

[0481] Method B

[0482]

[0483] Halide V can be coupled to tinane II using Stille coupling conditions to provide type VI compounds. Various additives, including (but not limited to) LiCl or CuI, can be optionally used to promote the reaction. Intramolecular ring closure of halide VI can be achieved using CH insertion cross-coupling conditions to provide type IV compounds. Potassium acetate or potassium neopentanoate are effective bases for the macrocyclization step.

[0484] Method C

[0485]

[0486] Nitropyridine VII can be reduced under Fe metal conditions to provide type VIII aminopyridine. In the case of an isoxazole moiety in the substrate, the yield can be improved by using SnCl2 conditions. Intramolecular cyclization of VIII can be achieved using a two-step one-pot borylation / Suzuki cross-coupling condition to provide type IX compounds.

[0487] Method D

[0488]

[0489] Nitropyridine X can be reduced under Fe metal conditions to provide XI-type aminopyridines. In the case of an isoxazole moiety in the substrate, the yield can be improved by using SnCl2 conditions. Intramolecular cyclization of XI can be achieved using CH insertion cross-coupling conditions to provide IX-type compounds. Potassium acetate or potassium neopentanoate are effective bases for the macrocyclization step.

[0490] Method E

[0491]

[0492] Alcohol XII can be reacted with chloropyrazine XIII under SNAr coupling conditions to form ether XIV. Intramolecular ring closure of XIV can be achieved using a two-step one-pot borylation / Suzuki cross-coupling condition to provide XV-type compounds.

[0493] Method F

[0494]

[0495] Alcohol XVI can be reacted with chloropyrazine XIII under SNAr coupling conditions to form ether XVII. Intramolecular ring closure of XVII can be achieved using CH insertion cross-coupling conditions to provide XV-type compounds. Potassium acetate or potassium neopentanoate are effective bases for the macrocyclization step.

[0496] Method G

[0497]

[0498] Aminopyridine XVIII can be brominated with a suitable brominating agent to provide bromide XIX. Desilylation of XIX using a suitable fluoride ion source, followed by intramolecular cyclization under two-step one-pot borylation / Suzuki cross-coupling conditions, yields the XX-type compound.

[0499] Method H

[0500]

[0501] Nitropyridine XXI can be reduced under Fe metal conditions to provide XXII-type aminopyridine. In the case of an isoxazole moiety in the substrate, the yield can be improved by using SnCl2 conditions. Intramolecular ring closure of XXII is achieved using CH insertion cross-coupling conditions, followed by TBAF demethylation and silylation to yield the XX-type compound. Potassium acetate or potassium neopentanoate is an effective base for the macrocyclization step.

[0502] Method I

[0503]

[0504] Nitropyridine XXIII can be converted to compound XI by reduction under Fe metal conditions followed by bromination with a suitable brominating agent. Intramolecular ring closure of XI can be achieved using CH insertion cross-coupling conditions to provide type IX compounds. Potassium acetate or potassium neopentanoate are effective bases for the macrocyclization step.

[0505] Method J

[0506]

[0507] Type XXIV compounds can be deprotected in solution by treatment with a suitable acid (e.g., TFA or HCl) to yield type IV compounds. Suitable protecting groups for this method include, but are not limited to, methoxymethyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, and p-methoxybenzyl.

[0508] Method K

[0509]

[0510] Nitropyridine XXV can be reduced under Fe metal conditions to provide type XI aminopyridine. In the case of an isoxazole moiety in the substrate, the yield can be improved by using SnCl2 conditions. Intramolecular cyclization of XI can be achieved using CH insertion cross-coupling conditions to provide type IX compounds. Potassium acetate or potassium neopentanoate are effective bases for the macrocyclization step.

[0511] Method L

[0512]

[0513] Nitropyridine X can be reduced with iron and then brominated with NBS to give XXVI-type aminopyridines. In the case of an isoxazole moiety in the substrate, the yield can be improved by using SnCl2 reduction conditions instead of iron. Intramolecular cyclization of XXVI can be achieved using a two-step one-pot boration / Suzuki cross-coupling condition to provide IX-type compounds.

[0514] Method M

[0515]

[0516] Type XXVII compounds can be deprotected first by hydrogenolysis on palladium on carbon under a hydrogen atmosphere, followed by alkylation of the resulting hydroxyl group with an alkyl halide (e.g., methyl iodide) to yield type XXVIII compounds. Suitable protecting groups for this method include, but are not limited to, benzyl and p-methoxybenzyl.

[0517] Method N

[0518]

[0519] Nitropyridine XXIX can be reduced under Fe metal conditions to provide XXX-type aminopyridines. In the case of an isoxazole moiety in the substrate, the yield can be improved by using SnCl2 conditions. Intramolecular ring closure of XXX can be achieved using CH insertion cross-coupling conditions to provide XXXI-type ketones. Potassium acetate or potassium neopentanoate are effective bases for the macrocyclization step. Ketone XXXI can be reduced to XXXII-type alcohols using sodium borohydride. Finally, deoxygenation can be performed using triethylsilane and trifluoroacetic acid to give the IX-type compound.

[0520] Those skilled in the art will recognize that, as illustrated in the following examples, the starting materials and reaction conditions can be altered, the reaction sequence changed, and additional steps employed to produce the compounds covered by this disclosure. In some cases, protecting certain reactive functional groups may be necessary to achieve some of the transformations described above. Generally, the need for such protecting groups and the conditions necessary for attaching and removing such groups are clear to experienced organic chemists. All disclosures in articles and references mentioned in this application, including patents, are incorporated herein by reference.

[0521] The following examples further illustrate the preparation of the compounds of this disclosure, and these examples should not be construed as limiting the scope or spirit of this disclosure to the specific procedures and compounds described herein.

[0522] Analytical methods

[0523] Use one of the following methods to collect LCMS data:

[0524]

[0525]

[0526]

[0527] Synthesis Examples

[0528] intermediate

[0529] Synthesis of 3-chloro-4-iodo-1H-pyrazole

[0530]

[0531] NIS (71.3 g, 317 mmol) was added in portions over 30 min at 0 °C to a stirred solution of 3-chloro-1H-pyrazole (25.00 g, 243.8 mmol) in DMF (250 mL). After addition, the mixture was stirred at 25 °C for 1 h and then concentrated by an oil pump to remove DMF. The residue was diluted with EtOAc, washed with saturated NaHCO3 (250 mL x 2) and brine (250 mL x 2), dried over Na2SO4 and concentrated to dryness to give crude 3-chloro-4-iodo-1H-pyrazole (55.7 g, 96%) as a brown oil. LC / MS (ESI) m / z: 229 [M+H] + .

[0532] The following intermediates were synthesized using a similar experimental protocol:

[0533]

[0534] Synthesis of 1-methyl-3-vinyl-1H-pyrazole

[0535]

[0536] At room temperature, K₂CO₃ (27.9 g, 202 mmol) and Pd(dppf)Cl₂ (0.98 g, 1.4 mmol) were added to a mixture of 3-iodo-1-methyl-1H-pyrazole (14.00 g, 67.31 mmol) and potassium vinyltrifluoroborate (27.06 g, 201.9 mmol) in 1,4-dioxane (200 mL) and water (50 mL). The mixture was degassed three times under a nitrogen atmosphere and stirred at 100 °C for 12 h. The mixture was filtered, and the filtrate was diluted with EtOAc (100 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EtOAc = 20:1) to give 1-methyl-3-vinyl-1H-pyrazole (4.25 g, 58% yield) as a yellow oil. LC / MS(ESI)(m / z): 109[M+H] + .

[0537] The following intermediates were synthesized using a similar experimental protocol:

[0538]

[0539]

[0540] Synthesis of (4-bromooxazol-5-yl)methanol

[0541]

[0542] Diisobutylaluminum hydride (1.5 M in THF, 45.5 mL, 68.2 mmol) was added dropwise to a solution of ethyl 4-bromooxazol-5-carboxylate (5.0 g, 22.7 mmol) in 100 mL of THF at 0 °C. The mixture was stirred at 0 °C for 2 h and then diluted with EA (50 mL). Water (3 mL) was added to the mixture first, followed by an aqueous solution of NaOH (15%, 3 mL), and then water (27 mL) was added again, all at 0 °C. After warming to room temperature, the mixture was stirred for 15 min, anhydrous MgSO4 was added, and stirring was continued for another 15 min. The mixture was then filtered to remove the solids. The filtrate was concentrated under vacuum to give crude (4-bromooxazol-5-yl)methanol (2.9 g, 72%) as a yellow solid. LC / MS ESI (m / z): 178 [M+H] + .

[0543] The following intermediates were synthesized using a similar experimental protocol:

[0544]

[0545]

[0546] Synthesis of 1-ethyl-3-iodo-1H-pyrazole

[0547]

[0548] Iodine ethane (12.4 mL, 155 mmol) and K₂CO₃ (21.4 g, 155 mmol) were added to a solution of 3-iodo-1H-pyrazole (10 g, 51.5 mmol) in DMF (50 mL) at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was filtered, and the filtrate was diluted with EtOAc (100 mL). The solution was washed with brine (3 x 30 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography (0 → 20% EA in PE) to give 1-ethyl-3-iodo-1H-pyrazole (8.4 g, yield: 73%) as a colorless oil. LC / MS (ESI) (m / z): 223 [M+H] + .

[0549] The following intermediates were synthesized using a similar experimental protocol:

[0550]

[0551]

[0552] Synthesis of 5-chloro-3-iodo-1-methyl-1H-pyrazole

[0553]

[0554] Iodomethane (0.03 mL, 0.5 mmol) was added to a mixture of 5-chloro-3-iodo-1H-pyrazole (100 mg, 0.440 mmol) and K₂CO₃ (121 mg, 0.880 mmol) in DMF (8 mL) at 25 °C. The mixture was then stirred at room temperature for 30 min. The reaction mixture was quenched with ice water, extracted twice into EA, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give crude 5-chloro-3-iodo-1-methyl-1H-pyrazole (100 mg, 94% yield) as a yellow liquid. The material can be used as is or purified by rapid chromatography, high-performance liquid chromatography, or supercritical fluid chromatography to separate possible positional isomers. LC / MS (ESI) m / z: 243 [M+H] + .

[0555] The following intermediates were synthesized using a similar experimental protocol:

[0556]

[0557] Synthesis of 5-bromo-4-iodo-1-methyl-1H-pyrazole

[0558]

[0559] LDA (2.0 M in THF, 28.8 mL, 57.7 mmol) was added dropwise to a solution of 4-iodo-1-methyl-1H-pyrazole (10.00 g, 48.08 mmol) in anhydrous THF (100 mL) over 20 min at -70 °C under a N2 atmosphere. After the addition, the mixture was stirred at -70 °C for 30 min, followed by the dropwise addition of CBr4 (19.0 g, 57.7 mmol) in THF (40 mL). The resulting mixture was stirred at -70 °C for 1 h. The mixture was quenched with saturated NH4Cl solution and then diluted with EA (200 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (2% EA in PE) to give the target product (11 g, yield: 80%) as a brown oil. LC / MS ESI (m / z): 287 [M+H] + .

[0560] The following intermediates were synthesized using a similar experimental protocol:

[0561]

[0562] Synthesis of 3-bromo-4-iodo-1-methyl-1H-pyrazole

[0563]

[0564] NIS (16.8 g, 74.5 mmol) was added to a solution of 3-bromo-1-methyl-1H-pyrazole (10.0 g, 62.1 mmol) in DMF (32 mL). After addition, the resulting solution was stirred at 50 °C for 5 h. The mixture was diluted with water and extracted into EA. The combined organic phases were washed with brine (30 mL × 4), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was purified by rapid chromatography (0 → 10% EA in PE) to give 3-bromo-4-iodo-1-methyl-1H-pyrazole (15.0 g, 76% yield) as a yellow solid. LC / MS (ESI) m / z: 287 [M+H] + .

[0565] The following intermediates were synthesized using a similar experimental protocol:

[0566]

[0567] Synthesis of 3-ethylisoxazole-5-carboxaldehyde

[0568]

[0569] DMP (16.01 g, 37.75 mmol) was added to a solution of (3-ethylisoxazole-5-yl)methanol (4.00 g, 31.5 mmol) in DCM (100 mL) at 0 °C, and the mixture was stirred at room temperature for 1 h (an additional equivalent of oxidant may be added to ensure complete oxidation of substrates containing multiple alcohol groups). The mixture was washed with saturated Na₂S₂O₃ (100 mL) and saturated NaHCO₃ (100 mL), dried over anhydrous Na₂SO₄, and concentrated to dryness. The residue was purified by rapid silica gel chromatography (20% EtOAc in PE) to give 3-ethylisoxazole-5-carboxaldehyde (3.37 g, yield: 86%) as a yellow oil. LC / MS (ESI): m / z = 126 [M+H] + .

[0570] The following intermediates were synthesized using a similar experimental protocol:

[0571]

[0572]

[0573] Synthesis of 4-(chloromethyl)-1-ethyl-1H-pyrazole

[0574]

[0575] SOCl2 (3.96 g, 33.3 mmol) was added dropwise to a solution of (1-ethyl-1H-pyrazole-4-yl)methanol (1.40 g, 11.1 mmol) in DCM (15 mL) at 0 °C under a nitrogen atmosphere. After addition, the mixture was stirred at 0 °C for 2 h. The mixture was concentrated to dryness to give crude 4-(chloromethyl)-1-ethyl-1H-pyrazole (1.60 g, 100% yield) as a yellow oil. LC / MS (ESI) m / z: 145 [M+H] + .

[0576] The following intermediates were synthesized using a similar experimental protocol:

[0577]

[0578] Synthesis of 5-(chloromethyl)-3-ethylisoxazole

[0579]

[0580] Triethylamine (5.8 mL, 42 mmol) was added to a stirred solution of (3-ethyl-1,2-oxazol-5-yl)methanol (4.10 g, 32.3 mmol) in anhydrous DCM (10 mL), followed by the addition of thionyl chloride (2.8 mL, 39 mmol) over a 10 min period at 0 °C. After the addition, the reaction mixture was stirred at room temperature under N2 for 5.0 h. The reaction mixture was cooled to 0 °C and quenched with a 10% NaCl aqueous solution. The mixture was then extracted twice with DCM, and the combined extracts were washed with a saturated NaHCO3 aqueous solution, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (10→30% EA in PE) to give 5-(chloromethyl)-3-ethyl-1,2-oxazol (4.20 g, yield: 90%) as a yellow oil. LC / MS ESI (m / z): 146 [M+H] + .

[0581] Synthesis of 3-bromo-1-methylpyrazole-4-carboxaldehyde

[0582]

[0583] POCl3 (12.00 mL) was added dropwise to a flask containing DMF (12.00 mL) at 0 °C. The resulting mixture was stirred at rt for 30 min. 3-Bromo-1-methylpyrazole (4.00 g, 24.8 mmol) was added dropwise to the mixture at room temperature. The resulting mixture was then stirred at 95 °C for 3 h. The reaction mixture was quenched with H2O at rt. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (C18, 0→30% MeCN + 0.1% FA in water) to give 3-bromo-1-methylpyrazole-4-carboxaldehyde (3.94 g, 84%) as a pale brown solid. LC / MS ESI (m / z): 189 [M+H] + .

[0584] Synthesis of 4-bromo-2-methylthiazol-5-carboxaldehyde

[0585]

[0586] At room temperature, K₂CO₃ (2.00 g, 14.8 mmol) and Pd(PPh₃)₄ (853 mg, 0.740 mmol) were added to a mixture of 2,4-dibromo-1,3-thiazol-5-carboxaldehyde (2.00 g, 7.38 mmol) and methylboronic acid (486 mg, 8.12 mmol) in 1,4-dioxane (20 mL). The mixture was degassed three times under N₂ and then stirred at 110 °C under N₂ atmosphere for 12 h. The reaction mixture was cooled to room temperature, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel, 25% EtOAc in PE) to give 4-bromo-2-methyl-1,3-thiazol-5-carboxaldehyde (728 mg, 31% yield) as a yellow solid. LC / MS (ESI) (m / z): 206 [M+H] + .

[0587] The following intermediates were synthesized using a similar experimental protocol:

[0588]

[0589] Synthesis of 5-bromoisothiazol-4-carboxylic acid

[0590]

[0591] t-BuLi (1.3M in heptane, 10.9mL, 14.3mmol) was added to a solution of isothiazol-4-carboxylic acid (800mg, 6.20mmol) in THF (15mL) at -78°C. Then, a solution of CBr4 (4.10g, 12.4mmol) in THF (10mL) was added dropwise. The mixture was stirred at -78°C for 2 hours. The reaction solution was quenched by adding a saturated aqueous NH4Cl solution and extracted with EtOAc. The aqueous layer was adjusted to pH 1 by adding an aqueous HCl solution (1M) and then extracted with EtOAc. The second organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give crude 5-bromoisothiazol-4-carboxylic acid (750mg) as a pale yellow oil. LC / MS ESI (m / z): 208 [M+H] + .

[0592] Synthesis of 5-iodo-1-methyl-3-vinyl-1H-pyrazole

[0593]

[0594] n-BuLi (24 mL, 58.95 mmol, 2.5 M in THF) was added dropwise to a stirred solution of 1-methyl-3-vinyl-1H-pyrazole (4.25 g, 39.30 mmol) in 40 mL of THF using a syringe at -78 °C under N2. After stirring at -78 °C for 1 h, a solution of iodine (14.97 g, 58.95 mmol) in 25 mL of THF was added, and the reaction mixture was stirred again at -78 °C under N2 for 2 h. The reaction mixture was then heated to 0 °C, quenched with saturated NH4Cl aqueous solution (25 mL), and extracted with EtOAc (25 mL x 2). The combined organic phases were washed with Na2S2O3 (20 mL), dried over anhydrous Na2SO4, and concentrated to dryness. The residue was purified by silica gel column chromatography (5% EtOAc in PE) to give 5-iodo-1-methyl-3-vinyl-1H-pyrazole (2.70 g, 29% yield) as a yellow oil. LC / MS (ESI) (m / z): 235.0 [M+H] + .

[0595] Synthesis of (5-iodo-1-methyl-1H-pyrazol-4-yl)methanol

[0596]

[0597] NaBH4 (84 mg, 2.5 mmol) was added to a mixture of 5-iodo-1-methyl-1H-pyrazole-4-carboxaldehyde (2.00 g, 8.47 mmol) in MeOH (30 mL) at -10 °C. The mixture was stirred at 20 °C for 1 h. The mixture was quenched with saturated NH4Cl (10 mL) and extracted with EA (60 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (5% MeOH in DCM) to give (5-iodo-1-methyl-1H-pyrazole-4-yl)methanol (840 mg, yield: 41%) as a pale yellow solid. LC / MS ESI (m / z): 239 [M+H] + .

[0598] The following intermediates were synthesized using a similar experimental protocol:

[0599]

[0600]

[0601] Synthesis of (3-iodo-1-methyl-1H-pyrazol-4-yl)methanol

[0602]

[0603] DIBAL-H (1.0 M in toluene, 12 mL, 12 mmol) was added dropwise to a solution of 3-iodo-1-methyl-1H-pyrazol-4-carboxaldehyde (2.00 g, 8.47 mmol) in anhydrous THF (20 mL) at -70 °C (an additional equivalent of reducing agent may be used if more than one hydride transfer is required). The mixture was stirred at -70 °C for 2 h, followed by quenching with a saturated aqueous NH4Cl solution. The resulting mixture was filtered, and the filter cake was washed with THF. The combined filtrates were concentrated under reduced pressure; the residue was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (0→20% EA in PE) to give (3-iodo-1-methyl-1H-pyrazol-4-yl)methanol (1.6 g, 79% yield) as a yellow oil. LC / MS ESI (m / z): 239 [M+H] + .

[0604] The following intermediates were synthesized using a similar experimental protocol:

[0605]

[0606] Synthesis of 3-chloro-1-ethyl-4-iodo-1H-pyrazole

[0607]

[0608] EtI (29.3 mL, 370 mmol) was added dropwise to a stirred mixture of 3-chloro-4-iodo-1H-pyrazole (55.34 g, 242.2 mmol) and Cs₂CO₃ (118.7 g, 364.1 mmol) in DMF (150 mL) at -10 °C. After stirring at -10 °C for 3 h, the reaction mixture was concentrated. The residue was diluted with EtOAc, washed with brine (150 mL x 2), dried over Na₂SO₄, and concentrated to dryness. The residue was purified by silica gel column chromatography (0→20% EA in PE) to give 3-chloro-1-ethyl-4-iodo-1H-pyrazole (37.5 g, 60%) as a yellow oil. LC / MS (ESI) m / z: 257 [M+H] + .

[0609] Synthesis of 4-(chloromethyl)-3-iodo-1-methyl-1H-pyrazole

[0610]

[0611] Thionyl chloride (0.90 mL, 13 mmol) was added to a solution of (3-iodo-1-methyl-1H-pyrazol-4-yl)methanol (1.00 g, 4.20 mmol) in DCM (20 mL) at 0 °C. After addition, the mixture was stirred at room temperature for 3 h and then concentrated to give crude 4-(chloromethyl)-3-iodo-1-methyl-1H-pyrazol (1.0 g, 93%) as a yellow oil. LCMS (ESI): m / z = 257 [M+H] + .

[0612] The following intermediates were synthesized using a similar experimental protocol:

[0613]

[0614] Synthesis of 1-ethyl-3-(propyl-2-yl)-1H-pyrazole

[0615]

[0616] K₂CO₃ (7.97 g, 57.6 mmol) and Pd(dppf)Cl₂ (1.05 g, 1.44 mmol) were added to a solution of 1-ethyl-3-iodo-1H-pyrazole (3.20 g, 14.4 mmol) in H₂O (0.5 mL) and 1,4-dioxane (2.5 mL) in a sealed tube. The mixture was stirred at 100 °C for 16 h, then poured into water (80 mL) and extracted with EA (80 mL). The organic layer was washed with brine (60 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1 to 1 / 1) to give 1-ethyl-3-(prop-1-en-2-yl)-1H-pyrazole (1.2 g, yield: 61%) as a white solid. LC / MS (ESI): m / z = 137.1 [M+H] + .

[0617] PtO2 (0.17 g, 0.73 mmol) was added to a solution of 1-ethyl-3-(prop-1-en-2-yl)-1H-pyrazole (1.0 g, 7.3 mmol) in EtOAc (15 mL), and the reaction mixture was stirred at room temperature under H2 (15 psi) for 16 h. The reaction mixture was filtered, and the filtrate was concentrated to give crude 1-ethyl-3-(prop-2-yl)-1H-pyrazole (800 mg, yield: 79%) as a white solid. LC / MS (ESI): m / z = 139.1 [M+H] + .

[0618] Synthesis of 1-(difluoromethyl)-1H-pyrazole-4-carboxaldehyde

[0619]

[0620] A mixture of 1H-pyrazole-4-carboxaldehyde (2.00 g, 20.8 mmol), diethyl(bromodifluoromethyl)phosphonate (9.45 g, 35.3 mmol), and KF (3.63 g, 62.4 mmol) in MeCN (20 mL) was stirred overnight at room temperature. The mixture was filtered and concentrated under vacuum to give a residue, which was purified by silica gel column chromatography (10% EtOAc in PE) to give 1-(difluoromethyl)-1H-pyrazole-4-carboxaldehyde (2.1 g, 69%) as a pale yellow oil. LC / MS (ESI) m / z: 147 [M+H] + .

[0621] The following intermediates were synthesized using a similar experimental protocol:

[0622]

[0623] Synthesis of 3-chloro-1-(cyclopropylmethyl)-1H-pyrazole

[0624]

[0625] To a solution of 3-chloro-1H-pyrazole (2.00 g, 19.5 mmol) in MeCN (50 mL), K₂CO₃ (5.40 g, 39.0 mmol) and (bromomethyl)cyclopropane (2.90 g, 21.5 mmol) were added. The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (0 → 30% EtOAc in PE) to give 3-chloro-1-(cyclopropylmethyl)-1H-pyrazole (2.3 g, 75%) as a colorless oil. LC / MS (ESI) (m / z): 157 [M+H] + .

[0626] The following intermediates were synthesized using a similar experimental protocol:

[0627]

[0628] Synthesis of 5-bromo-1-ethyl-1H-pyrazole-4-carboxaldehyde

[0629]

[0630] 1,3,5,7-Tetraazadamane (120 g, 857 mmol) was added to a solution of 5-bromo-1-ethyl-1H-pyrazole (100 g, 571 mmol) in TFA (700 mL) at 0 °C. The resulting mixture was stirred at 90 °C for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to remove most of the TFA. The residue was diluted with DCM (600 mL), washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (10% EtOAc in PE) to give 5-bromo-1-ethyl-1H-pyrazole-4-carboxaldehyde (60 g, yield: 52%) as a white solid. LC / MS ESI (m / z): 203 [M+H] + .

[0631] The following intermediates were synthesized using a similar experimental protocol:

[0632]

[0633]

[0634] Synthesis of 3-bromo-1-(tert-butyl)-1H-pyrazole

[0635]

[0636] H₂SO₄ (1.98 mL, 20.4 mmol) was slowly added to a mixture of 3-bromo-1H-pyrazole (3.00 g, 20.4 mmol) and 2-methylprop-2-ol (5 mL) at room temperature. The mixture was heated at 100 °C for 16 h. The reaction mixture was diluted with H₂O (20 mL) and then extracted with ethyl acetate (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (0→100% EtOAc in PE) to give 3-bromo-1-tert-butyl-1H-pyrazole (1.4 g, 34% yield) as a yellow oil. LC / MS (ESI) m / z: 203.0 [M+H] + .

[0637] Synthesis of 1,3-diethyl-1H-pyrazole

[0638]

[0639] A mixture of 3-vinyl-1-ethyl-1H-pyrazole (1.00 g, 8.18 mmol) and platinum dioxide (0.190 g, 0.82 mmol) in EtOAc (10 mL) was stirred overnight at room temperature under H2 (15 psi). The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0 → 100% EtOAc in PE) to give 1,3-diethyl-1H-pyrazole (1.00 g, 98% yield) as a colorless oil. LC / MS (ESI) (m / z): 125 [M+H] +

[0640] The following intermediates were synthesized using a similar experimental protocol:

[0641]

[0642] Synthesis of 3-(bromomethyl)-2-chloro-5-fluoropyridine

[0643]

[0644] Tribromophosphine (2.4 mL, 26 mmol) was added dropwise to a solution of (2-chloro-5-fluoropyridin-3-yl)methanol (4.0 g, 25 mmol) in DMF (20 mL) at 0 °C. After stirring at 25 °C for 1 h, the mixture was alkalized to pH 7 with saturated NaHCO3 and extracted with EA (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by preparative TLC (8% EA in PE) to give 3-(bromomethyl)-2-chloro-5-fluoropyridinium (2.7 g, 46% yield) as a colorless oil. LC / MS ESI (m / z): 224 [M+H] +

[0645] The following intermediates were synthesized using a similar experimental protocol:

[0646]

[0647] Synthesis of 1-cyclobutyl-4-iodo-1H-pyrazole

[0648]

[0649] A mixture of 4-iodo-1H-pyrazole (10.0 g, 51.6 mmol), bromocyclobutane (20.9 g, 155 mmol), and K₂CO₃ (28.5 g, 206 mmol) in DMF (200 mL) was heated at 70 °C for 12 h. The reaction mixture was filtered, and the filtrate was extracted with EA (300 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography (0 → 5% EtOAc in PE) to give the target product (9.73 g, 76% yield) as a yellow oil. LC / MS ESI (m / z): 249 [M+H] + .

[0650] The following intermediates were synthesized using a similar experimental protocol:

[0651]

[0652] Synthesis of (4-fluoro-2-iodophenyl)hydrazine

[0653]

[0654] Concentrated HCl (40 mL) was slowly added to a mechanically stirred solution of 4-fluoro-2-iodoaniline (5.0 g, 21 mmol) in AcOH (10 mL). The solution rapidly became a thick suspension. The reactants were then cooled to 0 °C in an ice bath and treated dropwise with a solution of sodium nitrite (1.63 g, 23.6 mmol) in water (8 mL). The reactants were stirred for 1 h, and then a solution of SnCl2 (8.46 g, 44.5 mmol) in concentrated HCl (8 mL) was slowly added. The reactants were heated to room temperature over 2 h. The suspension was filtered, washed with water, and dried under vacuum to give crude (4-fluoro-2-iodophenyl)hydrazine hydrochloride (4.1 g, yield: 77%) as a gray solid. LC / MS (ESI) m / z: 253 [M+H] + .

[0655] Synthesis of 5-bromo-4-(bromomethyl)-1-ethyl-1H-pyrazole

[0656]

[0657] A solution of tetrabromomethane (7.76 g, 23.4 mmol) in DCM was added dropwise to a stirred solution of (5-bromo-1-ethyl-1H-pyrazol-4-yl)methanol (4.00 g, 19.5 mmol) and triphenylphosphine (6.14 g, 23.4 mmol) in anhydrous DCM (50 mL) at 0 °C. After the addition, the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography (elution: PE / EtOAc 50 / 1 to 10 / 1) to give 5-bromo-4-(bromomethyl)-1-ethyl-1H-pyrazol (3.0 g, 57% yield) as a white solid. LC / MS ESI (m / z): 267 [M+H] + .

[0658] The following intermediates were synthesized using a similar experimental protocol:

[0659]

[0660] Synthesis of 2-bromo-3-(bromomethyl)-5-fluoropyridine

[0661]

[0662] A mixture of 2-bromo-5-fluoro-3-methylpyridine (2.00 g, 10.5 mmol), AIBN (52 mg, 0.32 mmol), and NBS (2.44 g, 13.7 mmol) in a DCE (20 mL) was degassed three times with N2 and heated to 85 °C for 1 h with stirring. After cooling to room temperature, the mixture was quenched with water, diluted with EtOAc, and washed with brine. The final organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum to provide the residue, which was purified by silica gel column chromatography (PE:EA = 50:1) to give 2-bromo-3-(bromomethyl)-5-fluoropyridine (1.20 g, 42%) as a white solid. LC-MS ESI (m / z): 268 [M+H] + .

[0663] The following intermediates were synthesized using a similar experimental protocol:

[0664]

[0665] Synthesis of 3-bromo-1-(difluoromethyl)-4-iodo-1H-pyrazole

[0666]

[0667] Potassium fluoride (2.3 g, 40 mmol) was added to a solution of 3-bromo-4-iodo-1H-pyrazole (5.42 g, 19.9 mmol) and diethyl (bromodifluoromethyl)phosphonate (7.95 g, 29.8 mmol) in acetonitrile (50 mL). The reaction mixture was stirred at 40 °C for 3 h. The mixture was cooled to room temperature, diluted with DCM (50 mL), washed with water (50 mL) and brine (50 mL), dried over Na₂SO₄, and concentrated to dryness. The residue was purified by silica gel chromatography (15% EtOAc in PE) to give 3-bromo-1-(difluoromethyl)-4-iodo-1H-pyrazole (5.12 g, 80% yield) as a white solid. LC / MS (ESI) m / z: 323 [M+H] + .

[0668] Synthesis of (3-cyano-1-methyl-1H-pyrazol-5-yl)boronic acid

[0669]

[0670] LDA (2M in THF, 4.7mL, 9.3mmol) was added dropwise to a solution of 1-methyl-1H-pyrazole-3-carboxynitrile (1.0g, 9.3mmol) in THF (15mL) at -78°C under a nitrogen atmosphere. After stirring at -78°C for 0.5h, a solution of trimethyl borate (1.9g, 19mmol) in THF (2mL) was added dropwise. After stirring at -78°C for 1h, the reaction mixture was quenched with a saturated aqueous ammonium chloride solution. The reaction mixture was diluted with EtOAc and washed first with H2O and then with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0→80% EtOAc in PE) to give (3-cyano-1-methyl-1H-pyrazole-5-yl)boronic acid (800mg, 57% yield) as a yellow oil. LC / MS ESI (m / z): 152 [M+H] + .

[0671] Synthesis of 3-(azidomethyl)-2-bromopyridine

[0672]

[0673] NaN3 (1.09 g, 16.8 mmol) was added to a solution of 2-bromo-3-(chloromethyl)pyridine (1.15 g, 5.58 mmol) in MeCN (20 mL) at room temperature. The mixture was stirred overnight at 40 °C and then partitioned between EtOAc (20 mL) and water (20 mL). The organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (silica gel, 0→33% EA in PE) to give 3-(azidomethyl)-2-bromopyridine (955 mg, 80% yield, in 2 steps) as a yellow oil. LC / MS (ESI) m / z: 213 [M+H] + .

[0674] The following intermediates were synthesized using a similar experimental protocol:

[0675]

[0676] Synthesis of 2-(5-bromo-1-ethyl-1H-pyrazol-4-yl)acetonitrile

[0677]

[0678] NaCN (2.20 g, 44.7 mmol) was added to a solution of 5-bromo-4-(chloromethyl)-1-ethyl-1H-pyrazole (5.00 g, 22.4 mmol) in DMSO (50 mL) at 25 °C. After stirring at 25 °C for 2 h, the mixture was treated with EtOAc and H2O. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (20% EtOAc in PE) to give 2-(5-bromo-1-ethyl-1H-pyrazole-4-yl)acetonitrile (4.5 g, yield: 94%) as a pale yellow oil. LC / MS ESI (m / z): 214 [M+H] + .

[0679] Synthesis of 1-(5-bromo-1-ethyl-1H-pyrazol-4-yl)ethanol

[0680]

[0681] Methyl magnesium bromide (18.8 mL, 56.4 mmol, 3.0 M in THF) was added dropwise to a solution of 5-bromo-1-ethyl-1H-pyrazole-4-carboxaldehyde (10.00 g, 49.25 mmol) in 120 mL of THF over 10 min at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The mixture was quenched with saturated NH4Cl (30 mL) at 0 °C and then extracted with EA (100 mL × 3). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (20% EtOAc in PE) to give 1-(5-bromo-1-ethyl-1H-pyrazole-4-yl)ethanol (9.28 g, 86% yield) as a pale yellow solid. LC / MS ESI (m / z): 219 [M+H] + .

[0682] The following intermediates were synthesized using a similar experimental protocol:

[0683]

[0684]

[0685] Synthesis of 3-(bromomethyl)-2-chloro-5-methoxypyridine

[0686]

[0687] NBS (565 mg, 3.17 mmol) and benzoyl peroxide (76.8 mg, 0.317 mmol) were added to a solution of 2-chloro-5-methoxy-3-methylpyridine (500 mg, 3.17 mmol) in CCl4 (12 mL). The mixture was stirred at 80 °C for 3 h, then poured into water (80 mL) and extracted with EA (80 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by eluting silica gel column chromatography (1→10% EtOAc in PE) to give 2-chloro-3-(dibromomethyl)-5-methoxypyridine (200 mg, yield: 20%) as a white solid. LC / MS (ESI): m / z = 315.8 [M+H] + .

[0688] Diethoxyphosphonic acid (0.161 mL, 1.27 mmol) and DIPEA (164 mg, 1.27 mmol) were added to a solution of 2-chloro-3-(dibromomethyl)-5-methoxypyridine (200 mg, 0.634 mmol) in THF (4 mL), and the reaction mixture was stirred at room temperature for 16 h. The mixture was poured into water (80 mL) and extracted with EA (80 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by eluting silica gel column chromatography (1→10% EtOAc in PE) to give 3-(bromomethyl)-2-chloro-5-methoxypyridine (100 mg, yield: 67%) as a white solid. LC / MS (ESI): m / z = 236 [M+H] + .

[0689] Synthesis of 1-(3-iodo-1-methyl-1H-pyrazol-4-yl)-prop-2-yn-1-ol

[0690]

[0691] Magnesium acetylenide (12.7 mL, 6.36 mmol) was added dropwise to a solution of 3-iodo-1-methyl-1H-pyrazol-4-carboxaldehyde (1.00 g, 4.24 mmol) in THF (7 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution (13 mL) and extracted with EA (15 mL × 3). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (20 → 90% EA in PE) to give 1-(3-iodo-1-methyl-1H-pyrazol-4-yl)prop-2-yn-1-ol (780 mg, 70%) as a white solid. LC-MS (ESI) m / z: 262.9 [M+H] + .

[0692] The following intermediates were synthesized using a similar experimental protocol:

[0693]

[0694]

[0695] Synthesis of 4-fluoro-2-iodobenzamide

[0696]

[0697] Oxaloyl chloride (5.00 g, 39.4 mmol) was added to a solution of 4-fluoro-2-iodobenzoic acid (5.00 g, 18.8 mmol) in 100 mL of DCM at 0 °C, followed by the addition of DMF (0.07 mL, 0.9 mmol). After the addition, the resulting mixture was stirred at 25 °C for 2 h. The mixture was concentrated under vacuum until dry to give crude 4-fluoro-2-iodobenzoyl chloride as a yellow oil.

[0698] A pre-cooled solution of NH3 aqueous solution (14 mL, 370 mmol, 28% in H2O) was added dropwise to a solution of 4-fluoro-2-iodobenzoyl chloride cooled to 0 °C in anhydrous DCM (50 mL) over 10 min. The internal temperature was kept below 5 °C during the addition. The resulting mixture was stirred at room temperature for 4 h and then concentrated to dryness. The remaining white solid was ground with water and PE and then dried in a vacuum oven to give the target product, 4-fluoro-2-iodobenzoamide (11 g, 92% yield, in 2 steps), as a white solid. LC / MS (ESI): m / z = 266 [M+H] + .

[0699] Synthesis of 3-bromo-5-methoxy-1-methyl-1H-pyrazole-4-carboxaldehyde

[0700]

[0701] Sodium methoxide (12.5 mL, 62.5 mmol, 5.0 M in methanol) was added to a stirred solution of 3,5-dibromo-1-methyl-1H-pyrazole-4-carboxaldehyde (5.00 g, 20.8 mmol) in MeOH (40 mL), and the resulting mixture was stirred at 60 °C for 1 h. After 1 h, the reaction mixture was concentrated under vacuum to remove the solvent. The residue was diluted with saturated aqueous solution of NH4Cl (30 mL) and EtOAc (30 mL), and then extracted with EtOAc (3 × 30 mL). The organic phases were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give crude 3-bromo-5-methoxy-1-methyl-1H-pyrazole-4-carboxaldehyde (3.31 g, yield: 59%) as a pale yellow solid. LC / MS (ESI) (m / z): 219 [M+H] + .

[0702] Synthesis of 1-(2,4-dibromothiazol-5-yl)prop-2-yn-1-ol

[0703]

[0704] Magnesium acetylenide (7.3 mL, 7.3 mmol, 1 M in THF) was added to a solution of 2,4-dibromo-1,3-thiazolyl-5-carboxaldehyde (2.0 g, 7.3 mmol) in THF (20 mL) at -78 °C under a nitrogen atmosphere. After addition, the mixture was stirred at -78 °C for 2 h. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (30 mL). The reaction mixture was concentrated under vacuum and diluted with DCM (30 mL). The mixture was then washed with brine (30 mL) and dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give a residue, which was purified by rapid chromatography (30% EtOAc in PE) to give 1-(2,4-dibromothiazolyl-5-yl)prop-2-yn-1-ol (1.5 g, 68%) as a white solid. LC / MS ESI (m / z): 296 [M+H] + .

[0705] The following intermediates were synthesized using a similar experimental protocol:

[0706]

[0707] Synthesis of 1-[(1-methylcyclopropyl)methyl]-1H-pyrazole-4-carboxaldehyde

[0708]

[0709] Methanesulfonyl chloride (0.49 mL, 6.4 mmol) was added to a solution of (1-methylcyclopropyl)methanol (0.56 mL, 5.8 mmol) and TEA (0.89 mL, 6.4 mmol) in DCM (20 mL). The mixture was stirred at 0 °C for 1 h. This solution was then added to a mixture of 1H-pyrazole-4-carboxaldehyde (836 mg, 8.70 mmol) and K₂CO₃ (1.60 g, 11.6 mmol) in DMF (10 mL), and the reaction mixture was stirred at 0 °C for 2 h. The mixture was filtered and concentrated under vacuum to give a residue, which was purified by silica gel column chromatography (25% EtOAc in PE) to give 1-[(1-methylcyclopropyl)methyl]-1H-pyrazole-4-carboxaldehyde (350 mg, yield: 37%) as a pale yellow solid. LC / MS ESI (m / z): 165 [M+H] + .

[0710] Synthesis of methyl 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxylate

[0711]

[0712] BH3·THF (61.9 mL, 61.9 mmol, 1N) was slowly added to a solution of 5-(methoxycarbonyl)-1-methyl-1H-pyrazole-3-carboxylic acid (5.70 g, 30.9 mmol) in THF (80 mL) at 0 °C under N2. The reactants were heated to room temperature over 30 min and then heated to 65 °C for 4 h. After cooling to room temperature, MeOH (12 mL) was slowly added, and the solvent was removed under reduced pressure. The residue was redissolved in MeOH (12 mL), stirred at room temperature for 20 min, and then evaporated to dryness. The residue was diluted with water and extracted with DCM (50.0 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude mixture was then purified by silica gel chromatography (33 in PE → 100% EA) to give methyl 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxylate (3.2 g, yield: 61%) as a white solid. LC-MSESI (m / z): 171 [M+H] + .

[0713] Synthesis of ethyl 5-ethyl-1,2-thiazolyl-3-carboxylate

[0714]

[0715] An ammonium acetate (3.36 g, 43.6 mmol) and AcOH (3.0 mL, 52 mmol) were added to a solution of ethyl 2,4-dioxohexanoate (3.00 g, 17.4 mmol) in toluene (30 mL). The reaction mixture was stirred at 80 °C for 18 h, cooled, and then concentrated under reduced pressure. The residue was diluted with water and the pH was adjusted to 8 with a 10% aqueous solution of Na₂CO₃. The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (0 → 20% EtOAc in PE) to give ethyl 4-amino-2-oxohexyl-3-enoate (1.2 g, 40%) as a pale yellow oil. LC / MS (ESI): m / z = 172 [M + H] + .

[0716] Phosphorus pentasulfide (0.84 g, 3.8 mmol) was added to a solution of ethyl 4-amino-2-oxohexyl-3-enoate (1.30 g, 7.59 mmol) in THF (15 mL). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated, and the residue was dissolved in EA (50 mL). The solution was cooled to 0 °C and H2O2 (30%, 5 mL) was added. The mixture was stirred at room temperature for 10 min and then extracted with EtOAc (50 mL x 2). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (0 → 30% EtOAc in PE) to give ethyl 5-ethyl-1,2-thiazolyl-3-carboxylate (0.75 g, 53%) as a white solid. LC / MS (ESI): m / z = 186 [M+H] + .

[0717] Synthesis of 1-(5-bromo-1-ethyl-1H-pyrazol-4-yl)acetone

[0718]

[0719] DMP (21.5 g, 50.8 mmol) was added in portions to a solution of 1-(5-bromo-1-ethyl-1H-pyrazole-4-yl)ethanol (9.28 g, 42.4 mmol) in DCM (50 mL) over 10 min at 0 °C. After addition, the mixture was stirred at 0 °C for another 10 min. The mixture was adjusted to pH 8 with saturated NaHCO3 and extracted with EA (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (20% EtOAc in PE) to give 1-(5-bromo-1-ethyl-1H-pyrazole-4-yl)acetone (8.6 g, yield: 93%) as a pale yellow oil. LC / MS ESI (m / z): 217 [M+H] + .

[0720] Synthesis of 4-bromo-3-methyl-1-(propyl-2-yl)-1H-pyrazole-5-carboxynitrile

[0721]

[0722] A mixture of 3-methyl-1-(prop-2-yl)-1H-pyrazole-5-carboxynitrile (470 mg, 3.15 mmol), TFA (0.25 mL, 3.4 mmol), and NBS (673 mg, 3.78 mmol) in MeCN (20 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (30 mL), washed with saturated Na2S2O3 (20 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid silica gel chromatography (25% EtOAc in PE) to give 4-bromo-3-methyl-1-(prop-2-yl)-1H-pyrazole-5-carboxynitrile (460 mg, 64% yield) as a pale yellow solid. LC / MS (ESI) m / z: 228 [M+H] + .

[0723] Synthesis of 5-bromo-N-methoxy-N-methylisothiazol-4-carboxamide

[0724]

[0725] To a solution of 5-bromoisothiazo-4-carboxylic acid (700 mg, crude) in DCM (15 mL), HATU (1.6 g, 4.4 mmol), TEA (1.0 g, 10 mmol), and N,O-dimethylhydroxylamine hydrochloride (427 mg, 4.40 mmol) were added. After stirring at 25 °C for 16 h, the reaction mixture was diluted with DCM. The resulting mixture was washed with H₂O, followed by washing with brine. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0→17% EtOAc in PE) to give 5-bromo-N-methoxy-N-methylisothiazo-4-carboxamide (220 mg, 14% yield, in 2 steps) as a yellow oil. LC / MS ESI (m / z): 251 [M+H] +。

[0726] The following intermediates were synthesized using a similar experimental protocol:

[0727]

[0728] Synthesis of 3-bromo-5-fluoro-2-(trimethylsilyl)pyridine

[0729]

[0730] A mixture of 2,3-dibromo-5-fluoropyridine (1.0 g, 3.9 mmol), hexamethyldistinane (1.35 g, 4.12 mmol), and Pd(PPh3)4 (0.23 g, 0.20 mmol) in toluene (50 mL) was heated to 110 °C under N2 for 16 h. The mixture was concentrated, diluted with EtOAc (50 mL), washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by neutralization Al2O3 chromatography (100% petroleum ether) to give 3-bromo-5-fluoro-2-(trimethylsilyl)pyridine (1.2 g, 90% yield) as a colorless oil. LC / MS (ESI) m / z: 340 [M+H] + .

[0731] Synthesis of methyl 3-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxylate

[0732]

[0733] Under a nitrogen atmosphere at 0 °C, 31.34 mL of 9-boronabicyclo[3.3.1]nonane (15.67 mmol) was added to a solution of methyl 3-vinyl-1-methyl-1H-pyrazole-5-carboxylate (1.50 g, 9.04 mmol) in dioxane (50 mL), and the mixture was stirred at 100 °C for 1 h. Water (10 mL), an aqueous solution of sodium hydroxide (3.50 mL, 31.0 mmol, 10% in water), and hydrogen peroxide (3.2 mL, 10% in water) were continuously added dropwise to the reaction mixture at 0 °C. The mixture was stirred at room temperature for 0.5 h, and then water (20 mL) and ethyl acetate (30 mL) were added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (1.6% MeOH in DCM) to give methyl 3-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxylate (1.10 g, 66%) as a white solid. LC / MS ESI (m / z): 185 [M+H] + .

[0734] Synthesis of methyl 2-chloro-4-methoxynicotinic acid

[0735]

[0736] A mixture of methyl 2,4-dichloropyridine-3-carboxylate (2.40 g, 11.6 mmol) and sodium methoxide (2.06 g, 11.6 mmol) in MeOH (20 mL) was refluxed under N2 for 16 h. The mixture was filtered through diatomaceous earth and the filtrate was diluted with EA (30 mL). The solution was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (0 → 30% EA in PE) to give methyl 2-chloro-4-methoxynicotinic acid (1.70 g, yield: 72%) as a white solid. LC / MS (ESI) (m / z): 202 [M+H] + .

[0737] Synthesis of potassium (E)-3-cyano-1-ethoxy-1-oxopent-2-ene-2-oate

[0738]

[0739] A solution of diethyl oxalate (10.57 g, 72.35 mmol) in THF (10 mL) was added via syringe to a stirred solution of t-BuOK (8.10 g, 72.4 mmol) and 18-crown-6 (1.91 g, 7.24 mmol) in THF (60 mL). The reaction mixture was heated to 60 °C, and then a solution of butyronitrile (5.00 g, 72.3 mmol) in THF (10 mL) was added, and stirring was continued at 60 °C for 30 min. The reaction mixture was evaporated to dryness to give a crude yellow solid of potassium (E)-3-cyano-1-ethoxy-1-oxopent-2-ene-2-ate (14.20 g, yield: 93%). LC / MS ESI (m / z): 170 [M+H] + .

[0740] Synthesis of 2-(2-bromo-4-fluorophenyl)-1H-imidazolium

[0741]

[0742] Under a nitrogen atmosphere at room temperature, NH3·H2O (113.8 mL, 738.9 mmol, 25% in H2O) was added dropwise to a mixture of 2-bromo-4-fluorobenzaldehyde (50.00 g, 246.3 mmol) and glyoxal (52.56 mL, 492.6 mmol, 40% in H2O) in EtOH (200 mL). After the addition, the resulting mixture was degassed, heated to 50 °C, and stirred for 72 h. The reaction mixture was concentrated under vacuum, and the residue was diluted with EA, washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by rapid silica gel column chromatography (PE / EA = 3:1 to 2:1) to give 2-(2-bromo-4-fluorophenyl)-1H-imidazolium (35.0 g, 59% yield) as a yellow solid. LC / MS ESI (m / z): 241 [M+H] + .

[0743] The following intermediates were synthesized using a similar experimental protocol:

[0744]

[0745] Synthesis of [5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl]methanol

[0746]

[0747] NaBH4 (0.33 g, 9.6 mmol) was added to a solution of 5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-carboxaldehyde (1.80 g, 7.41 mmol) in EtOH (15 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated, diluted with H2O (10 mL), and extracted with EtOAc (15 mL x 3). The combined organic solutions were washed with brine (15 mL), dried over anhydrous Na2SO4, and then concentrated to give crude (5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methanol (1.4 g, yield: 77%) as a pale yellow solid. LC-MS (ESI) m / z: 245 [M+H] + .

[0748] The following intermediates were synthesized using a similar experimental protocol:

[0749]

[0750] Synthesis of 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane

[0751]

[0752] 4-Methylbenzenesulfonic acid (1.69 g, 9.87 mmol) was added in a single step to a mixture of 2-bromo-5-fluorobenzaldehyde (10.0 g, 49.3 mmol) and ethane-1,2-diol (9.16 g, 148 mmol) in toluene (100 mL) under a nitrogen atmosphere at 25 °C. After the addition, the mixture was stirred at 120 °C for 16 h. The resulting mixture was cooled to 2–5 °C and then diluted with water and EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (20–30% EtOAc in PE) to give the target product (10.0 g, yield: 82%) as a yellow oil. LC / MS ESI (m / z): 247 [M+H] + .

[0753] Synthesis of 5-(cyclopropylmethyl)-3-iodo-1-methyl-1H-pyrazole

[0754]

[0755] TES (4.20 g, 36.0 mmol) and TFA (2.7 mL, 36 mmol) were added to a stirred solution of cyclopropyl(3-iodo-1-methyl-1H-pyrazol-5-yl)methanol (1.0 g, 3.6 mmol) in DCM (18 mL) at 0 °C. The reaction mixture was stirred overnight at room temperature. The mixture was concentrated to dryness. The residue was purified by rapid chromatography (0 → 10% EtOAc in PE) to give 5-(cyclopropylmethyl)-3-iodo-1-methyl-1H-pyrazol (0.60 g, 51% yield) as a yellow solid. LC / MS (ESI) (m / z): 263 [M+H] + .

[0756] The following intermediates were synthesized using a similar experimental protocol:

[0757]

[0758] Synthesis of (5-ethyl-1,2-thiazolyl-3-yl)methanol

[0759]

[0760] DIBAL-H (13.5 mL, 20.2 mmol) was added to a solution of ethyl 5-ethyl-1,2-thiazolyl-3-carboxylate (750 mg, 4.05 mmol) in THF (15 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h and then quenched by sequentially adding MeOH (0.5 mL) and then water (15 mL). The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (0 → 50% EtOAc in PE) to give (5-ethyl-1,2-thiazolyl-3-yl)methanol (510 mg, 88%) as a colorless oil. LC / MS (ESI): m / z = 144 [M+H] + .

[0761] The following intermediates were synthesized using a similar experimental protocol:

[0762]

[0763] Synthesis of 5-fluoro-2-(1H-imidazol-2-yl)benzaldehyde

[0764]

[0765] Over 30 min, n-BuLi (21.54 mL, 53.86 mmol, 2.5 N) and N,N-dimethylformamide (6.25 mL, 80.79 mmol) were simultaneously added dropwise via two separate syringes to a solution of 2-(2-bromo-4-fluorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (10.00 g, 26.93 mmol) in anhydrous THF (20 mL), while maintaining the internal temperature at -78 °C. After addition, the mixture was stirred at -78 °C for 10 min, followed by quenching with a saturated aqueous NH4Cl solution. The resulting mixture was slowly heated to room temperature and acidified to pH 6 with 2NHCl. The mixture was then extracted with diethyl ether (150 mL). The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel column chromatography (30% EtOAc in PE) to give 5-fluoro-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)benzaldehyde (6.0 g, 70% yield) as an orange oil. LC / MS ESI (m / z): 321 [M+H] + .

[0766] 5-Fluoro-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)benzaldehyde (45.0 g, 141 mmol) was added fractionally to a TFA (209 mL) flask at 20 °C. The resulting solution was stirred at room temperature for 6 h, and the reaction mixture was concentrated under vacuum to remove most of the TFA. The residue was slowly poured into a saturated aqueous solution of NaHCO3 at 0 °C. The resulting mixture was then extracted with EA (3 x 200 mL), and the combined extracts were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (0 → 3% MeOH in DCM) to give 5-fluoro-2-(1H-imidazol-2-yl)benzaldehyde (23.0 g, 86% yield) as a white solid. LC / MS ESI (m / z): 191 [M+H] + .

[0767] Synthesis of methyl 5-(cyclopropylmethyl)-1-methyl-1H-pyrazole-3-carboxylate

[0768]

[0769] A mixture of 5-(cyclopropylmethyl)-3-iodo-1-methyl-1H-pyrazole (2.50 g, 9.54 mmol), triethylamine (2.90 g, 28.6 mmol), MeOH (50 mL), and Pd(dppf)Cl2 (698 mg, 0.950 mmol) was degassed three times under a CO atmosphere and then stirred at 60 °C for 12 h under a CO balloon. The mixture was cooled to room temperature, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to give methyl 5-(cyclopropylmethyl)-1-methyl-1H-pyrazole-3-carboxylate (1.50 g, 81% yield) as a brown oil. LC / MS (ESI) (m / z): 195.1 [M+H] + .

[0770] The following intermediates were synthesized using a similar experimental protocol:

[0771]

[0772] Synthesis of 1-((4-bromothiazol-5-yl)methyl)-1H-imidazol-4-carboxynitrile

[0773]

[0774] DIAD (0.98 mL, 4.9 mmol) was added dropwise over 10 min at 0 °C to a mixture of (4-bromo-1,3-thiazolyl-5-yl)methanol (480 mg, 2.40 mmol), 1H-imidazolium-4-carboxynitrile (276 mg, 2.90 mmol), and triphenylphosphine (1.3 g, 4.9 mmol) in anhydrous THF (30 mL). After the addition, the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under vacuum, and the residue was purified by rapid silica gel chromatography (30% EtOAc in PE) to give 1-((4-bromothiazolyl-5-yl)methyl)-1H-imidazolium-4-carboxynitrile (220 mg, yield: 33%) as a pale yellow solid. LC / MS ESI (m / z): 269 [M+H] + .

[0775] The following intermediates were synthesized using a similar experimental protocol:

[0776]

[0777] Synthesis of 5-(2-bromo-4-fluorophenyl)-1,3,4-oxathiazol-2-one

[0778]

[0779] A solution of 2-bromo-4-fluorobenzamide (4.43 g, 20.3 mmol) in toluene (50 mL) was added to a chloro(chlorothioalkyl) methyl ketone (2.53 mL, 30.5 mmol). The mixture was stirred at 100 °C for 2 h, concentrated under vacuum, and the residue was purified by silica gel column chromatography (0→50% EtOAc in PE) to give 5-(2-bromo-4-fluorophenyl)-1,3,4-oxathiazol-2-one (3.90 g, 69% yield) as a white solid. LC / MS (ESI) m / z: 276 [M+H] + .

[0780] The following intermediates were synthesized using a similar experimental protocol:

[0781]

[0782] Synthesis of 5-ethyl-1,2-thiazolyl-3-carboxaldehyde

[0783]

[0784] MnO2 (3.10 g, 35.6 mmol) was added to a solution of (5-ethyl-1,2-thiazolyl-3-yl)methanol (510 mg, 3.56 mmol) in DCM (15 mL). The reaction mixture was stirred at room temperature for 20 h. After filtration, the filtrate was concentrated under reduced pressure to give 5-ethyl-1,2-thiazolyl-3-carboxaldehyde (120 mg, 24%) as a pale yellow oil. LC / MS (ESI): m / z = 142 [M+H] + .

[0785] The following intermediates were synthesized using a similar experimental protocol:

[0786]

[0787] Synthesis of methyl 3-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-5-carboxylate

[0788]

[0789] Diethylaminosulfur trifluoride (0.40 mL, 3.0 mmol) was slowly added to a crude solution of methyl 1-methyl-3-(2-oxoethyl)-1H-pyrazole-5-carboxylate (1.5 g, 2.9 mmol) in DCM (20 mL) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at this temperature for 0.5 h and then quenched with a saturated aqueous solution of NaHCO3 (50 mL). The resulting mixture was extracted with DCM (3 × 10 mL). The combined extracts were washed successively with water (1 × 30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (0 → 50% EtOAc in PE) to provide methyl 3-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-5-carboxylate (500 mg, 85%) as a white solid. LC / MS ESI (m / z): 205 [M+H] + .

[0790] The following intermediates were synthesized using a similar experimental protocol:

[0791]

[0792] Synthesis of (R)-1-(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)ethanol-1-ol

[0793]

[0794] A mixture of methyl[2-(methylamino)ethyl]amine (0.41 mL, 3.8 mmol), (1R)-1-(5-fluoro-2-iodophenyl)ethyl-1-ol (5.0 g, 19 mmol), 1H-pyrazole (1.09 mL, 22.6 mmol), K₂CO₃ (5.19 g, 37.6 mmol), and CuI (60 mg, 1.9 mmol) in NMP (150 mL) was stirred at 120 °C under N₂ for 18 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by column chromatography (silica gel, 1→10% ethyl acetate in petroleum ether) to give (1R)-1-[5-fluoro-2-(1H-pyrazol-1-yl)phenyl]ethane-1-ol (3.6 g, 93%) as a yellow oil. LC / MS (ESI) m / z: 207.1 [M+H] + .

[0795] The following intermediates were synthesized using a similar experimental protocol:

[0796]

[0797] Synthesis of ethyl 5-cyclobutyl-1-methyl-1H-pyrazole-3-carboxylate

[0798]

[0799] A solution of ethyl 4-cyclobutyl-2,4-dioxobutyrate (6.2 g, 31 mmol) in acetic acid (15 mL) was added to a mixture of methylhydrazine (3.6 g, 31 mmol), and the resulting mixture was stirred at 100 °C for 3 h. After 3 h, the reaction mixture was cooled to room temperature and concentrated under vacuum to remove the solvent, yielding a residue. The residue was diluted with toluene (20 mL) and concentrated under vacuum. The residue was purified by silica gel chromatography (0→50% EA in PE) to give ethyl 5-cyclobutyl-1-methyl-1H-pyrazole-3-carboxylate (4.2 g, 20%) as a yellow oil. LC / MS ESI (m / z): 209 [M+H] + .

[0800] Synthesis of 3-ethyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazole

[0801]

[0802] To a stirred solution of 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (5.00 g, 36.7 mmol) and 1-nitropropane (7.00 g, 78.6 mmol) in toluene (40 mL), phenyl isocyanate (17.0 mL, 119 mmol) was added, followed by triethylamine (2.94 mL, 21.2 mmol). The reaction mixture was heated to 120 °C and stirred for 24 h. After cooling to room temperature, the reaction mixture was quenched with 1 mL of water and stirred at room temperature for 1 h. The precipitate was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0→20% EtOAc in PE) to give 3-ethyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazole (10.0 g, 61% yield) as a yellow slurry. LC / MS ESI (m / z): 212 [M+H] + .

[0803] The following intermediates were synthesized using a similar experimental protocol:

[0804]

[0805] Synthesis of (2-(3-chloro-1H-pyrazol-1-yl)-5-fluorophenyl)methanol

[0806]

[0807] To a solution of (5-fluoro-2-iodophenyl)methanol (25.0 g, 99.2 mmol) in toluene (250 mL), 3-chloro-1H-pyrazole (11.2 g, 109 mmol), K₂CO₃ (27.4 g, 198.4 mmol), and CuI (1.9 g, 9.9 mmol) were added. The reaction mixture was stirred at 120 °C under N₂ for 12 h. The reaction mixture was filtered and concentrated. The residue was purified by rapid chromatography (5→25% EtOAc in PE) to give (2-(3-chloro-1H-pyrazole-1-yl)-5-fluorophenyl)methanol (21.1 g, 85% yield) as a white solid. LC / MS (ESI) (m / z): 227 [M+H] + .

[0808] Synthesis of 1-[(2-bromopyridin-3-yl)methyl]-1H-1,2,3-triazol-4-carboxylon

[0809]

[0810] A mixture of 3-(azidomethyl)-2-bromopyridine (955 mg, 4.48 mmol) and 2-chloropropion-2-enonitrile (0.90 mL, 11 mmol) in water (30 mL) was stirred at 80 °C for 12 h. The reaction mixture was cooled to room temperature, extracted with DCM (20 mL), washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid chromatography (silica gel, 0→100% EA in PE) to give 1-[(2-bromopyridin-3-yl)methyl]-1H-1,2,3-triazol-4-carboxynitrile (639 mg, 54% yield) as a white solid. LC / MS (ESI) m / z: 264 [M+H] + .

[0811] The following intermediates were synthesized using a similar experimental protocol:

[0812]

[0813] Synthesis of [5-bromo-1-(2-fluoroethyl)-1H-pyrazol-4-yl]methanol

[0814]

[0815] DIBAL-H (22.6 mL, 22.6 mmol, 1 M in toluene) was added dropwise to a solution of ethyl 5-bromo-1-(2-fluoroethyl)-1H-pyrazole-4-carboxylate (3.10 g, 11.3 mmol) in THF (50 mL) over 10 min at 0 °C. After the addition, the resulting solution was stirred at room temperature for another 3 h. After cooling to 0 °C, the reaction mixture was treated with EtOAc (100 mL) and 1 N HCl (100 mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (150 mL). The combined organics were concentrated under vacuum, and the residue was purified by rapid chromatography (silica gel, 0 → 50% EtOAc in PE) to give [5-bromo-1-(2-fluoroethyl)-1H-pyrazole-4-yl]methanol (2.1 g, 83% yield) as a white solid. LC-MS (ESI) measured value: 223 [M+H] + .

[0816] The following intermediates were synthesized using a similar experimental protocol:

[0817]

[0818] Synthesis of 3-bromo-4-[(4-ethylimidazol-1-yl)methyl]-1-methylpyrazole

[0819]

[0820] NaH (0.22 g, 9.1 mmol) was added dropwise to a stirred mixture of 4-ethyl-1H-imidazolium (0.73 g, 7.6 mmol) in DMF (5.00 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. 3-bromo-4-(chloromethyl)-1-methylpyrazole (1.91 g, 9.11 mmol) in DMF (5 mL) was added dropwise to the above mixture at 0 °C. The resulting mixture was stirred at room temperature for another 1 h, then quenched with H₂O. The mixture was directly purified by reversed-phase rapid chromatography (C18, 0→40% MeCN + 1% NH₃ aqueous solution) to give 3-bromo-4-[(4-ethylimidazol-1-yl)methyl]-1-methylpyrazole (1.9 g, 93%) as a pale brown oil. LC-MS (ESI) m / z: 269 [M+H] + .

[0821] Synthesis of (5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)methanol

[0822]

[0823] DIBAL-H (18.6 mL, 1 M in toluene) was added to a solution of ethyl 5-bromo-1-(difluoromethyl)-1H-pyrazole-4-carboxylate (2.00 g, 7.43 mmol) in THF (30 mL) over 30 min at -78 °C. The internal temperature was monitored during the addition to maintain it below -60 °C. The reaction mixture was stirred at -78 °C for 1 h, then quenched by slow addition to an aqueous HCl solution (1 M) at 0 °C. The mixture was extracted twice with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (30% EtOAc in PE) to give (5-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)methanol (1.5 g, 89% yield) as a colorless oil. LC / MS ESI (m / z): 227 [M+H] + .

[0824] Synthesis of (4-bromooxazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

[0825]

[0826] Add Desmond-Martin periodide (10.4 g, 24.4 mmol) to a solution of (4-bromooxazol-5-yl)methanol (2.90 g, 16.3 mmol) in DCM (5 mL). Stir the reaction mixture at room temperature for 2 h, filter, and concentrate the filtrate under vacuum. Purify the residue by rapid chromatography (0 → 30% EtOAc in PE) to give 4-bromooxazol-5-carboxaldehyde (2.49 g, 87% yield) as a pale yellow solid.

[0827] Isopropyl magnesium chloride-lithium chloride complex (13.1 mL, 17.0 mmol, 1.3 M in THF) was added dropwise to a solution of 1-ethyl-4-iodo-1H-pyrazole (3.14 g, 14.2 mmol) in 30 mL of THF at -10 °C. The mixture was stirred at room temperature for 1 h and then cooled to -10 °C. A solution of 4-bromooxazol-5-carboxaldehyde (2.49 g, 14.2 mmol) in 10 mL of THF was added dropwise. The ice bath was removed and stirring was continued at room temperature for 1 h. The reaction mixture was quenched with 20 mL of saturated aqueous NH4Cl solution and then extracted with EA (3 × 20 mL). The combined organic phases were washed with 20 mL of water and 20 mL of brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (0→10% MeOH in DCM) to give (4-bromooxazol-5-yl)(1-ethyl-1H-pyrazole-4-yl)methanol (1.21 g, 31% yield) as a pale yellow solid. LC / MS ESI (m / z): 272 [M+H] + .

[0828] Synthesis of (E)-1-(5-bromo-1-ethyl-1H-pyrazol-4-yl)-3-(dimethylamino)prop-2-en-1-one

[0829]

[0830] The mixture of 1-(5-bromo-1-ethyl-1H-pyrazol-4-yl)ethyl-1-one (4.00 g, 18.4 mmol) and DMF-DMA (80 mL) was stirred at 110 °C for 12 h. After cooling to room temperature, the mixture was concentrated under vacuum using an oil pump to obtain crude (E)-1-(5-bromo-1-ethyl-1H-pyrazol-4-yl)-3-(dimethylamino)prop-2-en-1-one (2.6 g, yield: 51%) as a pale yellow solid. LC / MS ESI (m / z): 272 [M+H] + .

[0831] The following intermediates were synthesized using a similar experimental protocol:

[0832]

[0833] Synthesis of 5-((4-bromothiazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carboxylon

[0834]

[0835] A mixture of 5-[(dibromo-1,3-thiazo-5-yl)methyl]-1-methyl-1H-pyrazole-3-carboxylonitrile (0.700 g, 1.93 mmol) and Pd / C (0.07 g, 10% wt) in MeOH (20 mL) was stirred for 2 h at 50 °C and 1 atm of H₂. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by rapid chromatography (0 → 25% EA in PE) to give 5-((4-bromothiazo-5-yl)methyl)-1-methyl-1H-pyrazole-3-carboxylonitrile (0.45 g, 78% yield) as a colorless oil. LC / MS (ESI) (m / z): 283 [M+H] +

[0836] Synthesis of (5-bromoisothiazo-4-yl)(1-ethyl-1H-1,2,3-triazol-4-yl)methanol

[0837]

[0838] Sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-oate (4.5 mg, 0.02 mmol), azidoethane (1.2 M in THF, 2.0 mL, 2.3 mmol), and CuSO4 (3.6 mg, 0.02 mmol) were added to a solution of 1-(5-bromoisothiazo-4-yl)prop-2-yn-1-ol (100 mg, 0.46 mmol) in t-BuOH (1 mL) and H2O (1 mL) at 25 °C under N2. After stirring at 50 °C for 16 h, the reaction mixture was diluted with EtOAc. The resulting mixture was washed with H2O and brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated. The residue was purified by rapid chromatography (silica gel, 0→100% EA in PE) to give a yellow oily substance (5-bromoisothiazol-4-yl)(1-ethyl-1H-1,2,3-triazol-4-yl)methanol (60 mg, 45% yield). LC / MS (ESI) m / z: 289 [M+H] +

[0839] The following intermediates were synthesized using a similar experimental protocol:

[0840]

[0841]

[0842] Synthesis of 1-((3-iodopyridin-4-yl)methyl)-1H-imidazol-4-carboxynitrile

[0843]

[0844] A solution of DIAD (1.1 g, 5.45 mmol) in THF (16 mL) was added to a solution of PPh3 (1.43 g, 5.45 mmol) in THF (16 mL) at 0 °C under a N2 atmosphere. After addition, the mixture was stirred at 0 °C until a white solid precipitated. 1H-imidazolium-4-carboxynitrile (304 mg, 3.27 mmol) in THF (8 mL) was added to the mixture, followed by (3-iodopyridin-4-yl)methanol (640 mg, 2.72 mmol) in THF (8 mL). The resulting mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure. The residue was diluted with DCM (60 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (50% EtOAc in PE) to give 1-((3-iodopyridin-4-yl)methyl)-1H-imidazol-4-carboxynitrile (890 mg, yield: 53%) as a pale yellow oil. LC-MS (ESI): m / z 311 [M+H] + .

[0845] The following intermediates were synthesized using a similar experimental protocol:

[0846]

[0847] Synthesis of 1-(4-fluoro-2-iodophenyl)-1H-pyrazole-3-carboxynitrile

[0848]

[0849] NaNO2 (2.93 g, 42.5 mmol) was added in several batches to a stirred flask containing concentrated H2SO4 (25 mL) at 0 °C. The mixture was heated to 50 °C and stirred at that temperature for 1 h. The nitrite mixture was cooled to 0 °C and allowed to stand. Concentrated H2SO4 (3.97 g, 40.5 mmol) was added separately to a solution of 4-fluoro-2-iodoaniline (9.60 g, 40.5 mmol) in AcOH (40 mL) at room temperature. This solution was added dropwise to the initial nitrite mixture at 0 °C. After the addition was complete, the mixture was heated to 50 °C for 1 h. The reaction mixture was then added at 5 °C to a suspension of ethyl 2,3-dicyanopropionate (9.24 g, 60.8 mmol) and anhydrous NaOAc (49.82 g, 607.6 mmol) in H2O (100 mL). After stirring at 15°C for 15 h, the reaction mixture was diluted with water and extracted with DCM (250 mL). The organic layer was stirred vigorously with 30% NH4OH aqueous solution (150 mL) for 2 h. The organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (0→70% EtOAc in PE) to give 5-amino-1-(4-fluoro-2-iodophenyl)-1H-pyrazole-3-carboxynitrile (11 g, 83%) as a brown solid. LC / MS ESI (m / z): 329 [M+H] +

[0850] A solution of 5-amino-1-(4-fluoro-2-iodophenyl)-1H-pyrazole-3-carboxynitrile (12.0 g, 36.6 mmol) and isoamyl nitrite (12.8 g, 110 mmol) in THF (150 mL) was heated to 70 °C at 25 °C and stirred for 16 h. The reaction mixture was diluted with EtOAc. The resulting mixture was washed with H2O and then with brine. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (0→20%) to give 1-(4-fluoro-2-iodophenyl)-1H-pyrazole-3-carboxynitrile (6.0 g, 52% yield) as a clear oil. LC / MS ESI (m / z): 314 [M+H] +。

[0851] Synthesis of 1-(4-fluoro-2-iodophenyl)-1H-pyrazole-5-carboxaldehyde

[0852]

[0853] Add [(1E)-4,4-dimethoxy-3-oxobut-1-en-1-yl]dimethylamine (2.82 g, 16.3 mmol) to a suspension of (4-fluoro-2-iodophenyl)hydrazine (4.10 g, 16.3 mmol) in EtOH (100 mL). Heat the resulting mixture under reflux for 48 h and then concentrate. Add 6N HCl (10 mL) to a solution of the crude residue in acetone (50 mL). Stir the resulting solution at room temperature for 30 min and then partition it between ethyl acetate and water. Wash the organic extract with water, saturated sodium bicarbonate, and brine, and then dry it with anhydrous sodium sulfate. Concentrate the residue to dryness to give crude 1-(4-fluoro-2-iodophenyl)-1H-pyrazole-5-carboxaldehyde (4.50 g, yield: 88%) as a black oil. LC / MS (ESI) m / z: 317 [M+H] + .

[0854] The following intermediates were synthesized using a similar experimental protocol:

[0855]

[0856]

[0857] Synthesis of 3,5-difluoro-2-iodo-N-methoxy-N-methylbenzamide

[0858]

[0859] A mixture of 3,5-difluoro-2-iodobenzoic acid (11.3 g, 39.8 mmol), EDCI (9.92 g, 51.7 mmol), HOBt (6.99 g, 51.7 mmol), methoxy(methyl)amine (2.92 g, 47.9 mmol), and DIPEA (15.40 g, 119.4 mmol) in DMF (40 mL) was stirred at room temperature for 2 h. The mixture was concentrated, diluted with EA (80 mL), and washed with saturated NaHCO3 (40 mL x 3). The combined organic layers were separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography to give 3,5-difluoro-2-iodo-N-methoxy-N-methylbenzamide (12 g, 92%) as a pale yellow solid. LC-MS (ESI): m / z 328 [M+H] + .

[0860] Synthesis of (5-cyclobutyl-1-methyl-1H-pyrazole-3-yl)methanol

[0861]

[0862] Diisobutylaluminum hydride (33.6 mL, 50.4 mmol, 1.5 M in THF) was added dropwise to a solution of ethyl 5-cyclobutyl-1-methyl-1H-pyrazole-3-carboxylate (4.20 g, 20.2 mmol) in THF (40 mL) at -78 °C. The mixture was stirred at -78 °C for 1 h. After 1 h, the reaction mixture was diluted with EA (20 mL), and then water (2 mL), NaOH aqueous solution (15%, 2 mL), and water (5 mL) were added sequentially at 0 °C. After warming to room temperature, anhydrous MgSO4 was added, and stirring was continued for 15 min. The mixture was filtered, and the filtrate was concentrated under vacuum to give crude (5-cyclobutyl-1-methyl-1H-pyrazole-3-yl)methanol (2.86 g, 85%) as a yellow oil. LC / MS ESI (m / z): 167 [M+H] + .

[0863] The following intermediates were synthesized using a similar experimental protocol:

[0864]

[0865] Synthesis of (3-ethylisoxazol-5-yl)methanol

[0866]

[0867] Amberlyst 15 (26 mg, 83 mmol) was added to a solution of 3-ethyl-5-[(ethylene oxide-2-yloxy)methyl]-1,2-oxazole (17.4 g, 82.4 mmol) in MeOH (10 mL). The mixture was stirred vigorously at 45 °C for 6 h. The solvent was removed by filtration and vacuum to give a red residue, which was purified by silica gel column chromatography (15 → ​​30% EtOAc in PE) to give (3-ethyl-1,2-oxazol-5-yl)methanol (8.05 g, yield: 77%) as a pale yellow oil. LC / MS ESI (m / z): 128 [M+H] + .

[0868] The following intermediates were synthesized using a similar experimental protocol:

[0869]

[0870] Synthesis of 3-(bromomethyl)-5-(cyclopropylmethyl)-1-methyl-1H-pyrazole

[0871]

[0872] A solution of phosphorus tribromide (2.00 g, 7.40 mmol) in DCM (5 mL) was added dropwise to a stirred solution of (410 mg, 2.47 mmol) of 5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-3-yl)methanol in DCM (10 mL) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 2 h, washed with saturated NaHCO3 (30 mL), dried over anhydrous Na2SO4, and evaporated to dryness. The residue was purified by silica gel column chromatography with PE / EtOAc (9:1→4:1) to give 3-(bromomethyl)-5-(cyclopropylmethyl)-1-methyl-1H-pyrazol (285 mg, 50% yield) as a yellow oil. LC / MS (ESI) (m / z): 229 [M+H] + .

[0873] Synthesis of 5-((2-chloropyridin-3-yl)methyl)-1-methyl-1H-pyrazole-3-carboxylon

[0874]

[0875] Na₂CO₃ (2.13 g, 20.1 mmol) was added to a solution of 3-(bromomethyl)-2-chloropyridine (2.07 g, 10.1 mmol), (3-cyano-1-methyl-1H-pyrazole-5-yl)boronic acid (1.52 g, 10.0 mmol), Pd(PPh₃)₄ (0.81 g, 0.70 mmol) in toluene (20 mL) and EtOH (4 mL). The reactants were degassed three times with N₂ and then stirred overnight at 100 °C. The mixture was cooled to room temperature, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (0 → 50% EtOAc in PE) to give 5-((2-chloropyridin-3-yl)methyl)-1-methyl-1H-pyrazole-3-carboxylonitrile (675 mg, 29%) as a yellow solid. LC / MS ESI (m / z): 233 [M+H] + .

[0876] The following intermediates were synthesized using a similar experimental protocol:

[0877]

[0878]

[0879] Synthesis of (5-bromo-1-cyclobutyl-1H-pyrazole-4-yl)methanol

[0880]

[0881] At -60°C, DIBAL-H (1M in toluene, 20.9 mL, 20.9 mmol) was added dropwise to a solution of ethyl 5-bromo-1-cyclobutyl-1H-pyrazole-4-carboxylate (1.9 g, 7.0 mmol) in THF (20 mL). The mixture was then stirred at 0°C for 3 h. The reaction mixture was diluted with EA (20 mL) and water (1 mL), and then 15% sodium hydroxide solution (1 mL) and water (2.5 mL) were added sequentially. After warming to room temperature, anhydrous magnesium sulfate was added and stirring was continued for 15 min. The resulting mixture was filtered, the filtrate was washed with saturated aqueous solution of NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0→10% EtOAc in PE) to give (5-bromo-1-cyclobutyl-1H-pyrazole-4-yl)methanol (1.6 g, 15%) as a pale yellow oil. LC / MS ESI (m / z): 231 [M+H] + .

[0882] Synthesis of 3-(benzyloxy)-5-bromo-1-ethyl-1H-pyrazole

[0883]

[0884] n-BuLi (27.3 mL, 68.3 mmol, 2.5 M in THF) was added to a stirred solution of 3-(benzyloxy)-1-ethyl-1H-pyrazole (11.5 g, 56.9 mmol) in 200 mL THF at -78 °C under N2. After stirring at -78 °C for 1 h, a solution of CBr4 (22.6 g, 68.2 mmol) in 50 mL THF was added. The reaction mixture was stirred at -78 °C for another 1.5 h, then quenched with saturated NH4Cl (50 mL) and concentrated under vacuum. The residue was purified by rapid chromatography (0 → 25% EtOAc in PE) to give 3-(benzyloxy)-5-bromo-1-ethyl-1H-pyrazole (8.3 g, 52% yield) as a yellow oil. LC / MS ESI (m / z): 281.0 [M+H] + .

[0885] The following intermediates were synthesized using a similar experimental protocol:

[0886]

[0887] Synthesis of (3-bromo-1-methyl-1H-pyrazole-4-yl)(5-ethylisoxazol-3-yl) methyl ketone

[0888]

[0889] i-PrMgBr (2.1 mL, 2.1 mmol, 1 M in THF) was added to a stirred solution of 3-bromo-4-iodo-1-methyl-1H-pyrazole (500 mg, 1.74 mmol) in 10 mL of THF at 0 °C under N2. After stirring at 0 °C for 1 h, a solution of 5-ethyl-N-methoxy-N-methyl-1,2-oxazol-3-carboxamide (360 mg, 1.95 mmol) in 2 mL of THF was added dropwise. The reaction mixture was stirred at 0 °C for another 1 h, then quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (30 mL x 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (25% EtOAc in PE) to give 3-(3-bromo-1-methyl-1H-pyrazole-4-carbonyl)-5-ethyl-1,2-oxazole (400 mg, 77% yield) as a yellow oil. LC / MS (ESI) (m / z): 284.3 [M+H] + .

[0890] Synthesis of 2-bromo-3-((4-ethyl-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridine

[0891]

[0892] Add 3-(azidomethyl)-2-bromo-5-fluoropyridine (350 mg, 1.52 mmol) and CuI (57 mg, 0.30 mmol) to a solution of 1-butyne (approximately 0.2 M, 12 mL). Stir the mixture at room temperature for 1 h, then filter through diatomaceous earth. Concentrate the filtrate under vacuum to obtain a residue, which is purified by silica gel column chromatography (PE:EA = 10:1 to 3:1) to give 2-bromo-3-[(4-ethyl-1H-1,2,3-triazol-1-yl)methyl]-5-fluoropyridine (130.0 mg, 30% yield) as a white solid. LC / MS (ESI): m / z = 285 [M+H] + .

[0893] Synthesis of (3-bromo-1-methyl-1H-pyrazole-4-yl)(3-ethylisoxazol-5-yl)methanol

[0894]

[0895] Isopropyl magnesium bromide (1M in THF, 5.48 mL, 5.48 mmol) was slowly added to a mixture of 3-bromo-4-iodo-1-methyl-1H-pyrazole (1.43 g, 4.98 mmol) in THF (10 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h. A solution of 3-ethylisoxazole-5-carboxaldehyde (0.62 g, 5.0 mmol) in anhydrous THF (3 mL) was added dropwise to the mixture at 0 °C over 10 min, and the resulting mixture was stirred at 0 °C for another 1 h. The reaction mixture was quenched with ice water and then extracted twice with EtOAc. The combined extracts were concentrated and the residue was purified by silica gel column chromatography (PE:EA = 3:1) to give a yellow oily substance (3-bromo-1-methyl-1H-pyrazole-4-yl)(3-ethylisoxazole-5-yl)methanol (900 mg, yield: 63%). LC / MS ESI (m / z): 286 [M+H] + .

[0896] The following intermediates were synthesized using a similar experimental protocol:

[0897]

[0898]

[0899]

[0900]

[0901] Synthesis of 5-bromo-4-((1-ethyl-1H-1,2,3-triazol-4-yl)methyl)isothiazole

[0902]

[0903] TES (193 mg, 1.60 mmol) was added to a solution of (5-bromoisothiazo-4-yl)(1-ethyl-1H-1,2,3-triazol-4-yl)methanol (60 mg, 0.20 mmol) in TFA (3 mL). The mixture was heated to 70 °C and stirred for 2 h. The reaction mixture was concentrated, diluted with a saturated aqueous solution of NaHCO3, and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (silica gel, 0→40% EA in PE) to give 5-bromo-4-((1-ethyl-1H-1,2,3-triazol-4-yl)methyl)isothiazolidinazole (50 mg, 88% yield) as a yellow oil. LC / MS (ESI) m / z: 273 [M+H] +

[0904] The following intermediates were synthesized using a similar experimental protocol:

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914] Synthesis of 4-bromo-5-((4-(difluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methylthiazole

[0915]

[0916] A solution of 1-((4-bromo-2-methylthiazol-5-yl)methyl)-1H-pyrazole-4-carboxaldehyde (580 mg, 2.03 mmol) in DAST (5 mL) was stirred at 30 °C under N2 for 12 h. The reaction mixture was quenched at 0 °C with a saturated aqueous solution of NaHCO3 (50 mL) and extracted with EtOAc (15 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (10→25% EtOAc in PE) to give 4-bromo-5-((4-(difluoromethyl)-1H-pyrazole-1-yl)methyl)-2-methylthiazolium (426 mg, 68% yield) as a yellow oil. LC / MS (ESI) (m / z): 308 [M+H] + .

[0917] Synthesis of 3,5-difluoro-2-iodobenzaldehyde

[0918]

[0919] DIBAL-H (36.7 mL, 39.7 mmol, 1.0 M) was added dropwise to a solution of 3,5-difluoro-2-iodo-N-methoxy-N-methylbenzamide (8.00 g, 24.5 mmol) in THF (60 mL) at -78 °C under a nitrogen atmosphere. After addition, the mixture was stirred at 0 °C for 2 h. The mixture was quenched with ice water and then extracted with DCM (40 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (5% DCM in MeOH) to give 3,5-difluoro-2-iodobenzaldehyde (6.0 g, 92%) as a yellow oil. LC-MS (ESI): m / z 269 [M+H] + .

[0920] The following intermediates were synthesized using a similar experimental protocol:

[0921]

[0922] Synthesis of [2-(1,3-dioxolane-2-yl)-4-fluorophenyl]trimethyltinane

[0923]

[0924] n-BuLi (1.78 mL, 4.45 mmol, 2.5 M) was added dropwise to a mixture of 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane (1.0 g, 4.0 mmol) in THF (20 mL) at -78 °C. The mixture was stirred at -78 °C for 1 h. Then, trimethyltin chloride (4.45 mL, 4.45 mmol, 1.0 M in THF) was added dropwise to the mixture. The resulting mixture was stirred at -78 °C for 15 min. The mixture was quenched with saturated NH4Cl (50 mL) at 0 °C and extracted with EtOAc (50 mL x 3). The combined extracts were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (10% EtOAc in PE) to give [2-(1,3-dioxolane-2-yl)-4-fluorophenyl]trimethylstanane (600 mg, yield: 44%) as a colorless oil. LC / MS ESI (m / z): 333 [M+H] + .

[0925] Synthesis of (5-bromo-1-methyl-1H-pyrazol-4-yl)(5-iodo-1-methyl-1H-pyrazol-4-yl)methanol

[0926]

[0927] Isopropyl magnesium bromide (1.0 M in THF, 13.9 mL, 13.9 mmol) was added dropwise to a solution of 5-bromo-4-iodo-1-methyl-1H-pyrazole (2.00 g, 6.99 mmol) in 35 mL of THF at -70 °C under a nitrogen atmosphere. After the addition, the mixture was stirred at -70 °C for 30 min, and then a solution of 5-iodo-1-methyl-1H-pyrazole-4-carboxaldehyde (2.14 g, 9.09 mmol) in 15 mL of THF was added dropwise over 10 min at -70 °C. The resulting mixture was stirred at -70 °C for another 2 h, and then diluted with a saturated aqueous solution of NH4Cl (60 mL). The mixture was extracted with DCM (2 x 100 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (30% EtOAc in PE) to give a yellow oily substance (5-bromo-1-methyl-1H-pyrazole-4-yl)(5-iodo-1-methyl-1H-pyrazole-4-yl)methanol (785 mg, yield: 29%). LC / MS ESI (m / z): 397 [M+H] + .

[0928] The following intermediates were synthesized using a similar experimental protocol:

[0929]

[0930] Synthesis of 1-(2-(1,3-dioxolane-2-yl)-4-fluorophenyl)-1H-pyrazole

[0931]

[0932] Copper oxide (348 mg, 2.43 mmol) was added to a solution of 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane (3.0 g, 12.1 mmol) in 1-methylpyrrolidine (50 mL) at room temperature, followed by the addition of 1H-pyrazole (868 mg, 12.8 mmol). After stirring overnight at 120 °C, the reaction mixture was diluted with EtOAc and water. The organic layer was separated, washed three times with saturated NH4Cl aqueous solution, washed once with brine, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (PE:EA = 10:1 to 1:1, V / V) to give 1-(2-(1,3-dioxolane-2-yl)-4-fluorophenyl)-1H-pyrazole (2.0 g, 70% yield) as a yellow oil. TLC:R f =0.3(PE / EA=5:1),LC / MS ESI(m / z):235[M+H] + .

[0933] The following intermediates were synthesized using a similar experimental protocol:

[0934]

[0935] Synthesis of 5-fluoro-2-(4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)benzaldehyde

[0936]

[0937] Add (4-fluoro-2-formylphenyl)boronic acid (1.69 g, 10.1 mmol), sodium carbonate (2.14 g, 20.2 mmol), and Pd(dppf)Cl2 (492 mg, 0.670 mmol) to a solution of (5-iodo-1-methyl-1H-pyrazole-4-yl)methanol (1.6 g, 6.7 mmol) in dioxane (15 mL) and H2O (5 mL). After stirring at 80 °C for 2 h, the reactants were diluted with water and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (silica gel, EtOAc / PE = 1 / 1) to give 5-fluoro-2-[4-(hydroxymethyl)-1-methyl-1H-pyrazole-5-yl]benzaldehyde (1.2 g, 76% yield) as a white solid. LC / MS ESI (m / z): 235 [M+H] + .

[0938] Synthesis of 3-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxynitrile

[0939]

[0940] LiTMP·MgCl2 (1.0 M in THF, 36.3 mL, 36.3 mmol) was added dropwise to a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxynitrile (5.40 g, 24.2 mmol) in THF (50 mL) at -16 °C under nitrogen atmosphere. The resulting solution was stirred at -16 °C for 1 h. Then N,N-dimethylformamide (3.7 mL, 48.4 mmol) was added and the mixture was stirred for 1 h. The reaction mixture was quenched by adding brine, extracted with EtOAc (2 x 30 mL), dried, and concentrated. The residue was purified by rapid chromatography (silica gel, 0–5% ethyl acetate in petroleum ether) to give 3-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxynitrile (3.4 g, 60%) as a brown liquid. LC / MS(ESI) m / z: 252 [M+H] + .

[0941] The following intermediates were synthesized using a similar experimental protocol:

[0942]

[0943] Synthesis of (2-chloropyridin-3-yl)(3-ethyl-1-methyl-1H-pyrazol-5-yl)methanol

[0944]

[0945] Isopropyl magnesium bromide (5.21 mL, 3.43 mmol) was added to a solution of 2-chloro-3-iodopyridine (1.04 g, 4.34 mmol) in THF (17 mL) at -5 °C. After stirring at room temperature for 0.5 h, 3-ethyl-1-methyl-1H-pyrazole-5-carboxaldehyde (600 mg, 4.34 mmol) was added. Stirring was continued at room temperature for another 0.5 h, and the mixture was then poured into water (80 mL) and extracted with EA (80 mL x 3). The organic layer was washed with saturated NaCl (60 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (30% EtOAc in PE) to give (2-chloropyridin-3-yl)(3-ethyl-1-methyl-1H-pyrazole-5-yl)methanol (850 mg, 78%) as a pale yellow solid. LC / MS(ESI): m / z = 252[M+H] + .

[0946] The following intermediates were synthesized using a similar experimental protocol:

[0947]

[0948]

[0949]

[0950] Synthesis of 2-chloro-3-((1-ethyl-1H-pyrazol-4-yl)methyl)-5-methoxypyridine

[0951]

[0952] To a solution of 3-(bromomethyl)-2-chloro-5-methoxypyridine (100 mg, 0.423 mmol) in THF (2.5 mL) and H₂O (0.5 mL), (1-ethyl-1H-pyrazol-4-yl)boronic acid (59 mg, 0.42 mmol), K₃PO₄ (269 mg, 1.27 mmol), and 1,1'-bis(di-t-butylphosphino)ferrocene palladium dichloride (28 mg, 0.042 mmol) were added. The mixture was stirred at 70 °C for 16 h, then poured into water (80 mL) and extracted with EA (80 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (10→50% EtOAc in PE) to give 2-chloro-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-methoxypyridine (100 mg, yield: 94%) as a white solid. LC / MS (ESI): m / z = 252 [M+H] + .

[0953] The following intermediates were synthesized using a similar experimental protocol:

[0954]

[0955] Synthesis of 2-chloro-3-((1-ethyl-1H-pyrazol-4-yl)methyl)-4-methoxypyridine

[0956]

[0957] CBr4 (853 mg, 2.58 mmol) and PPh3 (675 mg, 2.58 mmol) were added to a solution of (2-chloro-4-methoxypyridin-3-yl)methanol (447 mg, 2.58 mmol) in DCM (20 mL) at -10 °C. The mixture was stirred at -10 °C for 2 h. The reaction mixture was quenched with saturated NH4Cl aqueous solution at 0 °C and extracted with DCM (30 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (25% EA in PE) to give 3-(bromomethyl)-2-chloro-4-methoxypyridine (350 mg, yield: 58%) as a yellow oil. LC / MS (ESI) (m / z): 236 [M+H] + .

[0958] A mixture of 3-(bromomethyl)-2-chloro-4-methoxypyridine (250 mg, 1.06 mmol), 1-ethyl-4-(tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazole (234 mg, 1.06 mmol), K3PO4 (179 mg, 0.846 mmol), and Pd(dppf)Cl2 (28 mg, 0.042 mmol) in water (1 mL) and THF (5 mL) was stirred at 95 °C under a nitrogen atmosphere for 4 h. The reaction mixture was filtered, and the filtrate was diluted with EA (50 mL). The solution was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid column chromatography (0→30% EtOAc in PE) to give 2-chloro-3-((1-ethyl-1H-pyrazol-4-yl)methyl)-4-methoxypyridine (120 mg, yield: 45%) as a colorless oil. LC / MS (ESI) (m / z): 252 [M+H] + .

[0959] Synthesis of 4-bromo-5-((1-ethyl-1H-pyrazol-4-yl)methyl)oxazole

[0960]

[0961] Triethylsilane (3.60 mL, 22.2 mmol) was added to a solution of (4-bromooxazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol (1.21 g, 4.45 mmol) in trifluoroacetic acid (12 mL) and stirred at room temperature for 1.5 h. The reaction mixture was then concentrated under vacuum to obtain a residue, which was diluted with EA (20 mL) and alkalized to pH 7 with saturated aqueous NaHCO3 solution. The layers were separated, and the aqueous phase was extracted with EA (3 × 20 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (0 → 40% EtOAc in PE) to give 4-bromo-5-((1-ethyl-1H-pyrazol-4-yl)methyl)oxazole (678 mg, 60% yield) as a yellow oil. LC / MS ESI (m / z): 256 [M+H] + .

[0962] The following intermediates were synthesized using a similar experimental protocol:

[0963]

[0964]

[0965]

[0966]

[0967] Synthesis of (3-bromo-1-methyl-1H-pyrazole-4-yl)(5-ethylisoxazol-3-yl)methanol

[0968]

[0969] NaBH4 (65 mg, 1.9 mmol) was added to a stirred solution of 3-(3-bromo-1-methyl-1H-pyrazole-4-carbonyl)-5-ethyl-1,2-oxazole (400 mg, 1.41 mmol) in 10 mL of methanol at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1, V / V) to give (3-bromo-1-methyl-1H-pyrazole-4-yl)(5-ethyl-1,2-oxazole-3-yl)methanol (360 mg, 85% yield) as a white solid. LC / MS (ESI) (m / z): 286.0 [M+H] + .

[0970] The following intermediates were synthesized using a similar experimental protocol:

[0971]

[0972]

[0973] Synthesis of 5-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-3-ethylisoxazole

[0974]

[0975] Triethylsilane (4.06 mL, 25.2 mmol) and trifluoroacetic acid (2.34 mL, 31.5 mmol) were added to a solution of (3-bromo-1-methyl-1H-pyrazol-4-yl)(3-ethylisoxazol-5-yl)methanol (900 mg, 3.15 mmol) in dichloromethane (8 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. The solvent was removed under vacuum, and the residue was treated with water and EA. The organic layer was separated and concentrated under vacuum to give 5-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-3-ethylisoxazole (680 mg, yield: 80%) as a brown oil. LC / MS ESI (m / z): 270 [M+H] + .

[0976] The following intermediates were synthesized using a similar experimental protocol:

[0977]

[0978]

[0979]

[0980] Synthesis of (5-bromo-1-ethyl-1H-pyrazol-4-yl)(4-chloropyrimidin-5-yl)methanol

[0981]

[0982] n-BuLi (2.5 M in THF, 8.65 mL, 21.6 mmol) was added dropwise to a solution of 4-chloro-5-iodopyrimidine (2.60 g, 10.8 mmol) in THF (50 mL) at -78 °C under a nitrogen atmosphere. The mixture was stirred at -78 °C for 10 min, and then a solution of 5-bromo-1-ethyl-1H-pyrazole-4-carboxaldehyde (1.98 g, 9.73 mmol) in THF (10 mL) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 30 min. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl and then extracted with EA (100 mL × 2). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, 30% EtOAc in PE) to give (5-bromo-1-ethyl-1H-pyrazol-4-yl)(4-chloropyrimidin-5-yl)methanol (1.4 g, yield: 41%) as a yellow oil. LC / MS ESI (m / z): 317 [M+H] + .

[0983] Synthesis of 5-(hydroxy(3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-carboxynitrile

[0984]

[0985] Diisopropylamide lithium (4.20 mL, 8.40 mmol, 2.0 M in THF) was added dropwise to a solution of 1-methyl-1H-pyrazole-3-carboxynitrile (600 mg, 5.60 mmol) in THF (20 mL), and the mixture was kept at -78 °C for 1 h. After 1 h, a solution of 3-iodo-1-methyl-1H-pyrazole-4-carboxaldehyde (1.98 g, 8.40 mmol) in THF (15 mL) was added dropwise, and the resulting mixture was stirred at -78 °C for 2 h. The reaction mixture was quenched by adding 20 mL of saturated aqueous NH4Cl solution and then extracted with EA (3 × 20 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography using MeOH in DCM (0→5%, V / V) to give 0.94 g, 82%, a yellow solid of 5-(hydroxy(3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-carboxynitrile. LC / MS ESI (m / z): 344 [M+H] + .

[0986] The following intermediates were synthesized using a similar experimental protocol:

[0987]

[0988]

[0989] Synthesis of 3-cyclobutyl-5-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)isoxazole

[0990]

[0991] A mixture of 5-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-3-cyclobutylisoxazole (230 mg, 0.78 mmol), methyl[2-(methylamino)ethyl]amine (30 mg, 0.39 mmol), CuI (40 mg, 0.21 mmol), and KI (1.29 g, 7.79 mmol) in dioxane (5.0 mL) was stirred at 100 °C under N2 for 5 h. The mixture was diluted with water and extracted with EA (50 mL × 3). The combined extracts were washed twice with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (0 → 50% EA in PE) to give 3-cyclobutyl-5-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)isoxazole (220 mg, 78% yield) as a yellow oil. LC-MS (ESI): 344 [M+H] + .

[0992] The following intermediates were synthesized using a similar experimental protocol:

[0993]

[0994] Synthesis of tert-butyl 2-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)hydrazine-1-carboxylate

[0995]

[0996] A solution of 3-iodo-1-methyl-1H-pyrazol-4-carboxaldehyde (4.70 g, 19.9 mmol) and tert-butyl hydrazine carboxylate (2.63 g, 19.9 mmol) in MeOH (20 mL) was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give crude (E)-2-((3-iodo-1-methyl-1H-pyrazol-4-yl)methylene)hydrazine-1-carboxylate (6.80 g, 98% yield) as a yellow oil. LC / MS ESI (m / z): 351 [M+H] + .

[0997] NaBH3CN (1.22 g, 19.4 mmol) was added to a solution of (E)-2-((3-iodo-1-methyl-1H-pyrazol-4-yl)methylene)hydrazine-1-carboxylic acid tert-butyl ester (6.80 g, 19.4 mmol) in AcOH (20 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (20 mL), washed with saturated Na2CO3 (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10→30% EA in PE) to give 2-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)hydrazine-1-carboxylic acid tert-butyl ester (5.00 g, 73% yield) as a white solid. LC / MS ESI (m / z): 353 [M+H] + .

[0998] Synthesis of 5-chloro-3-iodo-(1-methyl-1H-pyrazol-4-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

[0999]

[1000] At 0 °C and under N2, isopropyl magnesium chloride-lithium chloride complex (1.88 mL, 2.45 mmol, 1.3 M in THF) was added dropwise to a solution of 1-ethyl-4-iodo-1H-pyrazole (502 mg, 2.26 mmol) in 4 mL of THF. The mixture was stirred for 1 h and then 5-chloro-3-iodo-1-methyl-1H-pyrazole-4-carboxaldehyde (510 mg, 1.89 mmol) in 1 mL of THF was added dropwise to the mixture at 0 °C. The mixture was heated to room temperature and stirred under N2 for 2 h. The reaction mixture was poured into water (100 mL) and extracted with EA (100 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, 1→10% EA in PE) to give 5-chloro-3-iodo-(1-methyl-1H-pyrazol-4-yl)(1-ethyl-1H-pyrazol-4-yl)methanol (420 mg, 61%) as a yellow solid. LC / MS (ESI) m / z: 367 [M+H] + .

[1001] The following intermediates were synthesized using a similar experimental protocol:

[1002]

[1003] Synthesis of (2,4-dibromothiazol-5-yl)(3-ethyl-1-methyl-1H-pyrazol-5-yl)methanol

[1004]

[1005] i-PrMgCl·LiCl (4.6 mL, 1.3 M in THF, 5.93 mmol) was added dropwise to a stirred solution of 3-ethyl-5-iodo-1-methyl-1H-pyrazole (1.40 g, 5.93 mmol) in 20 mL of THF at 0 °C under N2. After stirring at 0 °C for 1 h, a solution of 2,4-dibromothiazol-5-carboxaldehyde (1.77 g, 6.52 mmol) in 5 mL of THF was added at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, and LC-MS showed that the reaction was complete. The reaction mixture was quenched with saturated NH4Cl (15 mL), extracted with EtOAc (10 mL), dried over anhydrous Na2SO4, and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1) to give (2,4-dibromothiazol-5-yl)(3-ethyl-1-methyl-1H-pyrazole-5-yl)methanol (1.10 g, 49% yield), which was a yellow oil. LC / MS (ESI) (m / z): 379.9 [M+H] + .

[1006] The following intermediates were synthesized using a similar experimental protocol:

[1007]

[1008]

[1009] Synthesis of 1-(2-(1,3-dioxolane-2-yl)-4-fluorophenyl)-4-fluoro-1H-pyrazole

[1010]

[1011] At room temperature, 4-fluoro-1H-pyrazole (1.77 g, 20.6 mmol), cesium carbonate (9.14 g, 28.1 mmol), CuI (0.71 g, 3.7 mmol), and L-proline (0.43 g, 3.4 mmol) were added to a solution of 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane (4.62 g, 18.7 mmol) in DMF (20 mL). The mixture was degassed three times under N2 and stirred overnight at 120 °C. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was diluted with 50 mL of saturated aqueous NH4Cl solution and extracted with EtOAc (3 x 50 mL). The combined organic extracts were then washed with 3 x 30 mL of saturated aqueous NH4Cl solution and 30 mL of brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (silica gel, 0→10% EtOAc in PE) to give 1-(2-(1,3-dioxolane-2-yl)-4-fluorophenyl)-4-fluoro-1H-pyrazole (2.62 g, yield: 56%) as a brown oil. LC / MS (ESI) m / z: 253 [M+H] + .

[1012] Synthesis of 1-(2-(1,3-dioxolane-2-yl)-4-fluorophenyl)-3-fluoro-1H-pyrazole

[1013]

[1014] Add 3-fluoro-1H-pyrazole (0.53 g, 6.1 mmol), cesium carbonate (2.71 g, 8.32 mmol), and cuprous oxide (0.16 g, 1.1 mmol) to a solution of 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane (1.37 g, 5.54 mmol) in 1-methyl-2-pyrrolidone (5 mL), and stir the resulting mixture overnight at 120 °C. Cool the reaction mixture to room temperature and dilute with EA (5 mL) and saturated aqueous solution of NH4Cl (5 mL). Separate the layers and extract the aqueous phase with EA (3 × 5 mL). Wash the combined organic phases with saturated aqueous solution of NH4Cl (5 mL) and brine (5 mL), dry with anhydrous Na2SO4, filter, and concentrate under vacuum. The residue was purified by rapid chromatography (0→10% EA in PE) to give 1-(2-(1,3-dioxolane-2-yl)-4-fluorophenyl)-3-fluoro-1H-pyrazole (486 mg, 35%), a pale yellow oil. LC / MS ESI (m / z): 253 [M+H] + .

[1015] Synthesis of (Z)-4-(5-bromo-1-ethyl-1H-pyrazol-4-yl)-2-((dimethylamino)methylene)-3-oxobutyronitrile

[1016]

[1017] Concentrated H₂SO₄ (10 mL) was added dropwise to a mixture of 2-(5-bromo-1-ethyl-1H-pyrazol-4-yl)acetonitrile (4.50 g, 21.0 mmol) and MeOH (50 mL) at 25 °C. After stirring at 80 °C for 16 h, the mixture was slowly neutralized to pH 8 with saturated NaHCO₃ at 0 °C. The resulting mixture was extracted twice with EtOAc. The combined extracts were washed with H₂O and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0→20% EA in PE) to give methyl 2-(5-bromo-1-ethyl-1H-pyrazol-4-yl)acetate (3.3 g, yield: 64%) as a yellow oil. LC / MS ESI (m / z): 247 [M+H] +

[1018] Acetonitrile (822 mg, 20.0 mmol) and methyl 2-(5-bromo-1-ethyl-1H-pyrazol-4-yl)acetate (3.30 g, 13.4 mmol) were added to a solution of potassium 2-methylbutyrate (10.0 mL, 20.0 mmol, 2 M in THF) in anhydrous THF (50 mL) at 0 °C. After stirring at 25 °C for 16 h, the mixture was filtered, and the filter cake was collected and washed with hexane. The filter cake was dissolved in water and adjusted to pH 3 with aqueous HCl (1 N). The resulting mixture was then extracted twice with EtOAc. The combined organic extracts were washed with H2O and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give 4-(5-bromo-1-ethyl-1H-pyrazol-4-yl)-3-oxobutyronitrile (1.9 g, yield: 56%) as a brown oil. LC / MS ESI (m / z): 256 [M+H] +

[1019] DMF-DMA (1.50 g, 12.5 mmol) was added to a solution of 4-(5-bromo-1-ethyl-1H-pyrazol-4-yl)-3-oxobutyronitrile (1.6 g, 6.3 mmol) in 20 mL of THF at 25 °C. After stirring at 25 °C for 2 h, the reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give (Z)-4-(5-bromo-1-ethyl-1H-pyrazol-4-yl)-2-((dimethylamino)methylene)-3-oxobutyronitrile (1.1 g, yield: 56%) as a yellow solid. LC / MS (ESI) m / z: 311 [M+H] + .

[1020] Synthesis of 3-((2-chloropyridin-3-yl)methyl)-1-methyl-1H-pyrazole-5-carboxylon

[1021]

[1022] A mixture of 4-bromo-3-[(2-chloropyridin-3-yl)methyl]-1-methyl-1H-pyrazole-5-carboxylonitrile (270 mg, 0.87 mmol), PPh3 (46 mg, 0.17 mmol), K2CO3 (240 mg, 1.73 mmol), and Pd(OAc)2 (20 mg, 0.087 mmol) in n-BuOH (20 mL) was stirred overnight at 80 °C under N2. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was treated with water and extracted with EA (2 x 100 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by rapid silica gel column chromatography (PE:EA = 5:1) to give 3-((2-chloropyridin-3-yl)methyl)-1-methyl-1H-pyrazole-5-carboxylonitrile (70 mg, 31%) as a colorless oil. LC / MS(ESI): m / z = 233[M+H] + .

[1023] Synthesis of ethyl 3-(2-bromo-4-fluorophenyl)-1,2-oxazol-4-carboxylate

[1024]

[1025] Sodium hydroxide (4.40 g, 110 mmol) was added to a solution of 2-bromo-4-fluorobenzaldehyde (5.9 mL, 49 mmol) and hydroxylamine hydrochloride (10.0 g, 145 mmol) in EtOH (120 mL) and water (120 mL). The mixture was stirred overnight at room temperature. The reaction mixture was acidified to pH 5 with 1N HCl and then concentrated to remove EtOH. The residue was dissolved in EtOAc (120 mL), washed with brine (120 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to give N-[(2-bromo-4-fluorophenyl)methylene]hydroxylamine (10.74 g, 100% yield) as a white solid. LC / MS (ESI) m / z: 218 [M+H] + .

[1026] NCS (8.55 g, 64.0 mmol) was added to a solution of N-[(2-bromo-4-fluorophenyl)methylene]hydroxylamine (10.74 g, 49.25 mmol) in N,N-dimethylformamide (50 mL) at 0 °C. After stirring at room temperature for 2 h, the reaction mixture was concentrated. The residue was diluted with EtOAc (50 mL), washed with saturated NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to give crude (Z)-2-bromo-4-fluoro-N-hydroxyimine benzyl chloride (12.44 g, 100% yield) as a yellow oil. LC / MS (ESI) m / z: 252 [M+H] + .

[1027] TEA (6.00 g, 59.4 mmol) was added to a solution of 2-bromo-4-fluoro-N-hydroxyimine benzyl chloride (5.0 g, 20 mmol) and ethyl propionate-2-acetylacetate (1.94 g, 19.8 mmol) in toluene (50 mL). The mixture was stirred overnight at 50 °C, and then the reaction mixture was concentrated. The residue was diluted with EtOAc (50 mL), washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1) to give ethyl 3-(2-bromo-4-fluorophenyl)isoxazole-4-carboxylate as a yellow oil (in the form of a mixture containing two positional isomers, 4.62 g, 74% yield). LC / MS (ESI) m / z: 314 [M+H] + .

[1028] Synthesis of methyl 5-(2-bromo-4-fluorophenyl)-3-methyl-1,2-oxazol-4-carboxylate

[1029]

[1030] Methylamine (17.4 g, 224 mmol, 40% in water) was added to a stirred solution of methyl 3-oxobutyrate (20.0 g, 172 mmol) in MeOH (20 mL). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure to give crude (2E)-3-(methylamino)but-2-enoic acid methyl ester (18.0 g, 81% yield) as a colorless oil. LC / MS (ESI) m / z: 130 [M+H] + .

[1031] DMF (0.07 mL) was added dropwise to a solution of 2-bromo-4-fluorobenzoic acid (2.0 g, 9.1 mmol) in SOCl2 (10 mL) at 0 °C. The reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give crude 2-bromo-4-fluorobenzoyl chloride (2.0 g, 92% yield) as a colorless oil.

[1032] To a solution of (2E)-3-(methylamino)but-2-enoate methyl ester (1.0 g, 7.7 mmol) in THF (10 mL), pyridine (0.94 mL, 12 mmol) and 2-bromo-4-fluorobenzoyl chloride (1.80 g, 7.74 mmol) were added. The reaction mixture was stirred overnight at 20 °C and then concentrated under reduced pressure. The residue was purified by rapid column chromatography (0 → 30% EA in PE) to give (0.40 g, 16% yield) methyl (3E)-2-(2-bromo-4-fluorobenzoyl)-3-(methylimino)butyrate as a colorless oil. LC / MS (ESI) m / z: 330 [M+H] + .

[1033] A mixture of (3E)-2-(2-bromo-4-fluorobenzoyl)-3-(methylimino)butyrate (400 mg, 1.21 mmol) and hydroxylamine hydrochloride (126 mg, 1.82 mmol) in AcOH (5 mL) was stirred at 110 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by rapid column chromatography (0→20% EA in PE) to give methyl 5-(2-bromo-4-fluorophenyl)-3-methyl-1,2-oxazol-4-carboxylate (300 mg, 79% yield) as a colorless oil. LC / MS (ESI): m / z = 314 [M+H] + .

[1034] Synthesis of 5,7-difluoro-3-methylbenzo[c][1,2]oxaporborane-1(3H)-ol

[1035]

[1036] i-PrMgBr (6.8 mL, 6.8 mmol, 1 M) was added dropwise to a solution of 1-(3,5-difluoro-2-iodophenyl)ethyl-1-ol (1.00 g, 3.52 mmol) in 30 mL of THF at -40 °C under a nitrogen atmosphere. After the addition, the mixture was stirred at -10 °C for 0.5 h, and then a solution of trimethyl borate (1.0 M in THF, 8.8 mL, 8.8 mmol) was added at -10 °C. The resulting mixture was stirred at room temperature for 16 h. The mixture was quenched with ice water and then extracted with EA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (PE:EA = 2:1) to obtain 5,7-difluoro-3-methyl-1,3-dihydro-2,1-benzoborazole-1-ol (700 mg, 95%) as a colorless oil. LC-MS (ESI): m / z 185 [M+H] + .

[1037] Synthesis of ethyl 3-(2-bromo-4-fluorophenyl)isothiazol-4-carboxylate

[1038]

[1039] Ethyl propargyl 2-acetylacetate (3.48 g, 35.5 mmol) was added dropwise to a solution of 5-(2-bromo-4-fluorophenyl)-2H-1,3,4-oxathiazol-2-one (4.90 g, 17.8 mmol) in toluene (50 mL) at room temperature. The reaction mixture was stirred at 120 °C for 16 h, concentrated under vacuum, and the residue was purified by rapid chromatography (0 → 30% EA in PE) to give ethyl 3-(2-bromo-4-fluorophenyl)isothiazol-4-carboxylate (1.7 g, 29% yield) as a white solid. LC / MS (ESI) m / z: 330 [M+H] + .

[1040] Synthesis of ethyl 1-(4-fluoro-2-iodophenyl)-1H-imidazolium-5-carboxylate

[1041]

[1042] Add ethyl 2-oxoacetate (10.01 mL, 50.63 mmol, 50% in toluene) to a solution of 4-fluoro-2-iodoaniline (10.00 g, 42.19 mmol) in MeOH (100 mL) and heat the resulting mixture under reflux for 3.5 h. Concentrate the mixture under vacuum and dissolve the resulting residue in anhydrous ethanol (100 mL) and treat with 1-isocyanomethylsulfonyl-4-methylbenzene (12.35 g, 63.28 mmol) and K₂CO₃ (11.66 g, 84.38 mmol). Heat the resulting mixture to 65 °C and stir for 4 h, then cool to room temperature and pour into water and EtOAc. The organic layer was separated and concentrated under reduced pressure, and purified by rapid silica gel chromatography (0→30% EtOAc in PE) to give ethyl 1-(4-fluoro-2-iodophenyl)-1H-imidazolium-5-carboxylate (11 g, 72% yield) as a yellow solid. LC / MS (ES+): m / z = 361 [M+H] + .

[1043] Synthesis of 1-(4-fluoro-2-iodophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-amine

[1044]

[1045] Concentrated HCl (10 mL) was added dropwise to a solution of 4,4,4-trifluoro-3-oxobutyronitrile (4.00 g, 29.2 mmol) and (4-fluoro-2-iodophenyl)hydrazine hydrochloride (10.1 g, 35.0 mmol) in EtOH (100 mL) at 25 °C. The mixture was stirred at 80 °C for 16 h, and the reaction mixture was neutralized to pH 8 with NaHCO3 and then diluted with EtOAc. The resulting mixture was washed with H2O and brine. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (0→17%) to give 1-(4-fluoro-2-iodophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-amine (5 g, 38% yield) as a brown solid. LC / MS ESI (m / z): 372 [M+H] +。

[1046] The following intermediates were synthesized using a similar experimental protocol:

[1047]

[1048] Synthesis of ethyl 3-(4-fluoro-2-iodophenyl)isothiazol-4-carboxylate

[1049]

[1050] Ethyl propargyl 2-acetylacetate (1.76 mL, 17.3 mmol) was added to a solution of 5-(4-fluoro-2-iodophenyl)-2H-1,3,4-oxathiazol-2-one (2.80 g, 8.66 mmol) in toluene (30 mL). The resulting solution was stirred in a sealed tube at 120 °C for 16 h. The mixture was concentrated under vacuum, and the residue was purified by rapid silica gel chromatography (EA / PE = 1 / 5) to give ethyl 3-(4-fluoro-2-iodophenyl)-1,2-thiazol-4-carboxylate (650 mg, 20%) as a colorless oil. LC / MS (ESI): m / z = 378 [M+H] + .

[1051] Synthesis of 2-chloro-3-((4-(cyclopropylmethyl)-1H-pyrazol-1-yl)methyl)pyridine

[1052]

[1053] Triethylsilane (2.4 mL, 15.1 mmol) was added to a solution of (1-((2-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)(cyclopropyl)methanol (400 mg, 1.5 mmol) in TFA (2 mL). The resulting mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was alkalized to pH 7 with saturated aqueous NaHCO3 solution and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (PE:EtOAc = 1:1, V / V) to give 2-chloro-3-((4-(cyclopropylmethyl)-1H-pyrazol-1-yl)methyl)pyridine (250 mg, 67%) as a yellow oil. LC / MS (ESI) (m / z): 248 [M+H] + .

[1054] Synthesis of 5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-4-chloropyrimidine

[1055]

[1056] POCl3 (1.58 g, 10.3 mmol) was added dropwise to a solution of 5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)pyrimidin-4-ol (970 mg, 3.43 mmol) in MeCN (30 mL) at 0 °C under a nitrogen atmosphere. After addition, the mixture was stirred at 80 °C for 3 h. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM (100 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (30% EtOAc in PE) to give 5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-4-chloropyrimidin (587 mg, yield: 57%) as a yellow solid. LC / MS ESI (m / z): 301 [M+H] + .

[1057] Synthesis of (3-bromo-1-(tert-butyl)-1H-pyrazol-4-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

[1058]

[1059] n-BuLi (1.30 mL, 3.25 mmol, 2.5 M in THF) was slowly added to a solution of 1-ethyl-4-iodo-1H-pyrazole (961 mg, 4.33 mmol) in 10 mL of THF at -78 °C, and the reaction mixture was stirred at -78 °C for 40 min (an additional equivalent of base may be used if the substrate contains additional acidic protons). Then, 3-bromo-1-(tert-butyl)-1H-pyrazole-4-carboxaldehyde (500 mg, 2.16 mmol) was added dropwise in 5 mL of THF at -78 °C, and the reaction mixture was stirred at -78 °C for 0.5 h. The reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid silica gel column chromatography (PE:EtOAc = 1:1) to give (3-bromo-1-(tert-butyl)-1H-pyrazole-4-yl)(1-ethyl-1H-pyrazole-4-yl)methanol (283 mg, 40% yield), a yellow oil. LC / MS ESI (m / z): 327 [M+H] + .

[1060] The following intermediates were synthesized using a similar experimental protocol:

[1061]

[1062]

[1063]

[1064]

[1065]

[1066] Synthesis of 4-(hydrazylmethyl)-3-iodo-1-methyl-1H-pyrazole hydrochloride

[1067]

[1068] HCl (30 mL, 4 N in dioxane) was added to a solution of tert-butyl 2-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)hydrazine-1-carboxylate (5.00 g, 14.2 mmol) in MeOH (20 mL) at room temperature. The mixture was stirred at 25 °C for 12 h and then concentrated under reduced pressure to give 4-(hydrazylmethyl)-3-iodo-1-methyl-1H-pyrazol hydrochloride (3.30 g, 75% yield) as a white solid. LC / MS ESI (m / z): 253 [M+H] + .

[1069] The following intermediates were synthesized using a similar experimental protocol:

[1070]

[1071] Synthesis of (R)-1-(5-fluoro-2-iodophenyl)ethyl benzoate

[1072]

[1073] DIAD (0.89 mL, 4.5 mmol) was added dropwise to a mixture of (1S)-1-(5-fluoro-2-iodophenyl)ethyl-1-ol (1.00 g, 3.76 mmol), benzoic acid (0.550 g, 4.51 mmol), and triphenylphosphine (1.18 g, 4.51 mmol) in THF (30 mL) at 0 °C under N2. The resulting mixture was stirred overnight at room temperature, poured into water, and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, 1–5% ethyl acetate in petroleum ether) to give (1R)-1-(5-fluoro-2-iodophenyl)ethyl benzoate (1.2 g, 86%) as a yellow solid. LC / MS (ESI): m / z = 371 [M+H] + .

[1074] The following intermediates were synthesized using a similar experimental protocol:

[1075]

[1076] Synthesis of tert-butyl 2-(4-fluoro-2-iodobenzoyl)hydrazine-1-carboxylate

[1077]

[1078] EDCI (6.14 g, 32.0 mmol), HOBT (4.32 g, 3.02 mmol), and TEA (6.46 g, 64.0 mmol) were added to a solution of 4-fluoro-2-iodobenzoic acid (8.50 g, 32.0 mmol) in DCM (50 mL). The mixture was stirred at room temperature for 0.5 h. Then, tert-butyl hydrazide carboxylate (5.07 g, 38.3 mmol) was added. The reaction mixture was stirred at room temperature for 16 h, quenched with water, and extracted with EA (100 mL). The organic layer was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (0 → 30% EA in PE) to give tert-butyl 2-(4-fluoro-2-iodobenzoyl)hydrazide-1-carboxylate (7.6 g, 63%) as a white solid. LC / MS (ESI): m / z = 381 [M+H] + .

[1079] Synthesis of 5-bromo-1-(cyclopropylmethyl)-4-[(2-iodo-4-methyl-1H-imidazol-1-yl)methyl]-3-methyl-1H-pyrazole

[1080]

[1081] K₂CO₃ (1.12 g, 8.08 mmol) was added to a solution of 5-bromo-4-(chloromethyl)-1-(cyclopropylmethyl)-3-methyl-1H-pyrazole (639 mg, 2.42 mmol) and 2-iodo-4-methyl-1H-imidazole (420 mg, 2.02 mmol) in DMF (5 mL). The mixture was stirred at 25 °C for 16 h. The reactants were concentrated and the residue was diluted with EtOAc (45 mL). The mixture was washed with brine (15 mL), dried over Na₂SO₄, and then concentrated. The residue was purified by rapid column chromatography (silica gel, 30–85% EtOAc in PE) to give 5-bromo-1-(cyclopropylmethyl)-4-[(2-iodo-4-methyl-1H-imidazole-1-yl)methyl]-3-methyl-1H-pyrazole (500 mg, yield: 57%) as a pale yellow solid. LC-MS(ESI) m / z: 435 [M+H] + .

[1082] The following intermediates were synthesized using a similar experimental protocol:

[1083]

[1084]

[1085] Synthesis of ethyl 3-bromo-1-(4-fluoro-2-iodophenyl)-1H-pyrazole-5-carboxylate

[1086]

[1087] Concentrated HCl (257 mg, 2.50 mmol) was added to a solution of (4-fluoro-2-iodophenyl)hydrazine hydrochloride (600 mg, 2.08 mmol) in H₂O (10 mL), followed by dropwise addition of a 50% aqueous solution of 2-oxoacetic acid (339 mg, 2.29 mmol) at 15 °C. The resulting mixture was stirred at 15 °C for 0.5 h. The precipitate was collected by filtration, washed with H₂O, and dried under vacuum to give crude (2E)-2-[2-(4-fluoro-2-iodophenyl)hydrazine-1-yl]acetic acid (500 mg, 78%) as a pale yellow solid. LC / MS (ESI) m / z: 309 [M+H] + .

[1088] NBS (5.20 g, 29.2 mmol) was added to a solution of (E)-2-(2-(4-fluoro-2-iodophenyl)hydrazine)acetic acid (4.50 g, 14.6 mmol) in DMF (30 mL) at -10 °C, and the mixture was stirred at -10 °C for 30 min. The reactants were filtered and concentrated under vacuum. The residue was purified by rapid chromatography (0 → 5% EtOAc in PE) to give (dibromomethyl)(4-fluoro-2-iodophenyl)diazepine (1.78 g, 27% yield) as a grayish-white solid. LC / MS (ESI) m / z: 421 [M+H] + .

[1089] A solution of ethyl propargyl ester (0.75 mL, 4.5 mmol) in DCM (2 mL) was added dropwise to a solution of (dibromomethyl)(4-fluoro-2-iodophenyl)diazeline (1.76 g, 4.17 mmol) and TEA (1.26 g, 12.5 mmol) in DMF (30 mL) at -10 °C. The reaction mixture was stirred at -10 °C for 10 min, then filtered and concentrated under vacuum. The residue was purified by rapid chromatography (0 → 20% EtOAc in PE) to give ethyl 3-bromo-1-(4-fluoro-2-iodophenyl)-1H-pyrazole-5-carboxylate (1.2 g, 62% yield) as a grayish-white solid. LC-MS (ESI): 439 [M+H] + .

[1090] Synthesis of 1-(4-fluoro-2-iodophenyl)-5-iodo-3-(trifluoromethyl)-1H-pyrazole

[1091]

[1092] A solution of 1-(4-fluoro-2-iodophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-amine (5.00 g, 13.4 mmol) in THF (80 mL) was added dropwise to a mixture of KI (6.70 g, 40.4 mmol) and isoamyl nitrite (4.70 g, 40.4 mmol) in THF (100 mL) at 0 °C. After stirring at 85 °C for 16 h, the reaction mixture was diluted with EtOAc. The resulting mixture was washed with H2O and brine. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (0 → 40% EtOAc in PE) to give 1-(4-fluoro-2-iodophenyl)-5-iodo-3-(trifluoromethyl)-1H-pyrazole (3.7 g, 57% yield) as a clear oil. LC / MS ESI (m / z): 483 [M+H] +。

[1093] Synthesis of (R)-5-fluoro-3-methylbenzo[c][1,2]oxaporborane-1(3H)-ol

[1094]

[1095] A solution of NaOH (32 mg, 0.81 mmol) in water (8 mL) was added to a solution of (1R)-1-(5-fluoro-2-iodophenyl)ethyl benzoate (300 mg, 0.81 mmol) in methanol (8 mL). The mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by column chromatography (silica gel, 1–5% ethyl acetate in petroleum ether) to give (1R)-1-(5-fluoro-2-iodophenyl)ethyl-1-ol (150 mg, 70%) as a white solid. LC / MS (ESI): m / z = 267 [M + H] + .

[1096] A 1.3 M solution (72.3 mL, 94.0 mmol) of the isopropyl magnesium chloride-lithium chloride complex in THF was added dropwise to a mixture of (1R)-1-(5-fluoro-2-iodophenyl)ethyl-1-ol (10.00 g, 37.59 mmol) in THF (120 mL) at -40 °C under N2. The mixture was stirred at -40 °C under N2 for 1 h, then heated to -10 °C and held for 0.5 h, followed by dropwise addition of trimethyl borate (10.67 mL, 93.97 mmol) over 10 min at -10 °C. After stirring overnight at room temperature under N2, the reaction mixture was poured into a saturated NH4Cl solution (100 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, 1→10% ethyl acetate in petroleum ether) to give (R)-5-fluoro-3-methylbenzo[c][1,2]oxaporborane-1(3H)-ol (4.0 g, 64%) as a colorless oil. LC / MS (ESI): m / z = 167 [M+H] + .

[1097] Synthesis of 3-(4-fluoro-2-iodophenyl)-1,2-thiazol-4-carboxaldehyde

[1098]

[1099] MnO2 (1.42 g, 16.4 mmol) was added to a solution of [3-(4-fluoro-2-iodophenyl)-1,2-thiazol-4-yl]methanol (550 mg, 1.64 mmol) in DCM (20 mL) at room temperature. The reaction mixture was then stirred at 40 °C for 32 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (30% EtOAc in PE) to give 3-(4-fluoro-2-iodophenyl)-1,2-thiazol-4-carboxaldehyde (400 mg, 73%) as a pale yellow solid. LC / MS (ESI): m / z = 334 [M+H] + .

[1100] Synthesis of 3-(1-(5-fluoro-2-iodophenyl)ethoxy)-2-nitropyridine

[1101]

[1102] NaH (1.38 g, 34.6 mmol, 60% in mineral oil) was added dropwise to a solution of 1-(5-fluoro-2-iodophenyl)ethyl-1-ol (9.20 g, 34.6 mmol) in THF (180 mL) over 10 min at 0 °C. After the addition, the mixture was stirred at 0 °C for 15 min, and then a solution of 3-fluoro-2-nitropyridine (4.91 g, 34.6 mmol) in THF (20 mL) was added dropwise. The ice bath was removed, and the mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between DCM (200 mL) and water (200 mL). The organic layer was separated, washed with brine, and concentrated under vacuum. The residue was purified by rapid chromatography (elution buffer: 0→30% EtOAc in PE) to give 3-(1-(5-fluoro-2-iodophenyl)ethoxy)-2-nitropyridine (5.3 g, yield: 39%) as a white solid. LC / MS ESI (m / z): 389 [M+H] +

[1103] The following intermediates were synthesized using a similar experimental protocol:

[1104]

[1105]

[1106]

[1107]

[1108]

[1109]

[1110]

[1111]

[1112]

[1113]

[1114]

[1115]

[1116]

[1117]

[1118]

[1119]

[1120]

[1121]

[1122]

[1123]

[1124] Synthesis of 4-((2-chloropyridin-3-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carboxylon

[1125]

[1126] SOCl2 (0.34 mL, 4.7 mmol) was added to a solution of 4-((2-chloropyridin-3-yl)(hydroxy)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carboxylonitrile (450 mg, 1.56 mmol) in 15 mL of DCM at 0 °C under N2. After stirring at room temperature for 2 h, the reaction mixture was concentrated to give crude 4-(chloro(2-chloropyridin-3-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carboxylonitrile (478 mg, 99% yield) as a colorless oil.

[1127] Zinc powder (1.08 g, 15.6 mmol) was added to a stirred solution of 4-(chloro(2-chloropyridin-3-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carboxylonitrile (478 mg, 1.56 mmol) in AcOH (12 mL). The reaction mixture was stirred at room temperature under N2 for 2 h and then concentrated under vacuum. The residue was purified by rapid silica gel column chromatography (30% EtOAc in PE) to give 4-((2-chloropyridin-3-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carboxylonitrile (160 mg, 38% yield) as a white solid. LC / MS (ESI) (m / z): 273 [M+H] + .

[1128] Synthesis of (5-(4-fluoro-2-formylphenyl)-1-methyl-1H-pyrazole-4-yl)methylmethanesulfonate

[1129]

[1130] TEA (65 mg, 0.64 mmol) was added to a solution of 5-fluoro-2-[4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl]benzaldehyde (50 mg, 0.20 mmol) in DCM (5 mL) at 0 °C, followed by the addition of MsCl (37 mg, 0.32 mmol). After stirring at room temperature for 1 h, the reaction mixture was quenched with water and extracted twice with DCM. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid chromatography (silica gel, EtOAc / PE = 2 / 1) to give a yellow solid of (5-(4-fluoro-2-formylphenyl)-1-methyl-1H-pyrazol-4-yl)methylmethanesulfonate (25 mg, 38% yield). LC / MS ESI (m / z): 313 [M+H] + .

[1131] The following intermediates were synthesized using a similar experimental protocol:

[1132]

[1133] Synthesis of 5-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)isoxazole-3-carboxamide

[1134]

[1135] NH3 was added dropwise to a solution of ethyl 5-((3-bromo-1-methyl-1H-pyrazole-4-yl)methyl)isoxazole-3-carboxylate (1.10 g, 3.50 mmol) in 2 mL MeOH via a syringe at room temperature. After stirring in a sealed tube at room temperature for 3 h, the reactants were evaporated to give crude 5-((3-bromo-1-methyl-1H-pyrazole-4-yl)methyl)isoxazole-3-carboxamide (920 mg, 92% yield) as a white solid. LC / MS (ESI) (m / z): 285 [M+H] + .

[1136] Synthesis of 3-bromo-4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-1-(difluoromethyl)-1H-pyrazol

[1137]

[1138] A solution of (3-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)(1-(cyclopropylmethyl)-1H-pyrazole-4-yl)methanol (340 mg, 0.979 mmol) in TFA (2.0 mL) and TES (1.0 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated. The residue was diluted with EtOAc (15 mL), washed with saturated NaHCO3 (20 mL) and brine (15 mL), dried over anhydrous Na2SO4, and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1) to give 3-bromo-4-((1-(cyclopropylmethyl)-1H-pyrazole-4-yl)methyl)-1-(difluoromethyl)-1H-pyrazole (300 mg, yield: 93%) as a yellow oil. LC / MS (ESI) m / z: 331 [M+H] + .

[1139] Synthesis of 2-(2-bromo-4-fluorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazolium

[1140]

[1141] NaH (12.94 g, 323.6 mmol, 60% in mineral oil) was added dropwise to a solution of 2-(2-bromo-4-fluorophenyl)-1H-imidazole (65.0 g, 270 mmol) in DMF (300 mL) over 0.5 h at 0 °C. After the addition, the mixture was stirred at 0 °C for 30 min and then heated to room temperature and stirred for 1 h. After cooling to 0 °C, [2-(chloromethoxy)ethyl]trimethylsilane (50.21 mL, 283.1 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched at 0 °C with 200 mL of saturated aqueous NH4Cl solution and then extracted with EA (2 x 300 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (30% EtOAc in PE) to give 2-(2-bromo-4-fluorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazolium (64 g, 64% yield) as a yellow solid. LC / MS ESI (m / z): 371 [M+H] + .

[1142] The following intermediates were synthesized using a similar experimental protocol:

[1143]

[1144]

[1145] Synthesis of 3-[(1R)-1-(5-fluoro-2-iodophenyl)ethoxy]pyridine-2-amine

[1146]

[1147] A mixture of (R)-3-(1-(5-fluoro-2-iodophenyl)ethoxy)-2-nitropyridine (15.5 g, 40.0 mmol), iron powder (22.4 g, 400 mmol), and NH4Cl (21.6 g, 400 mmol) in a co-solvent of EtOH (550 mL) and H2O (110 mL) was stirred at 80 °C for 1 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with DCM (500 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (50% EtOAc in PE) to give 3-[(1R)-1-(5-fluoro-2-iodophenyl)ethoxy]pyridine-2-amine (10.5 g, yield: 73%) as a white solid. LC / MS ESI (m / z): 359 [M+H] + .

[1148] The following intermediates were synthesized using a similar experimental protocol:

[1149]

[1150] Synthesis of 3-((4-chloropyridin-3-yl)met...

Claims

1. A compound of formula (I), or an enantiomer or mixture thereof, or a pharmaceutically acceptable salt thereof: (I) in Q is CH or N; Z is either CR5 or N; X is a 5-membered heteroaryl group, selected from the following groups: , , , , , , , , , and ; * indicates the junction of X with the methylene group bonded to X and Y; Y is selected from the following 5- or 6-membered heteroaryl groups. , , , , , , , , , , , , , , and ; Where * represents the junction of Y with the methylene group bonded to X and Y; R1 is selected from the group consisting of H, methyl, and hydroxymethyl; Each instance of R2 is independently selected from the following groups: H, CN, halogen, OC. 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Haloalkyl, CH2-C 3-4 cycloalkyl, C 3-6 cycloalkyl and three- to six-membered heterocyclic groups; Each instance of R3 is independently selected from the following groups: H, halogen, CN, OC. 1-4 Alkyl, C 1-4 Halogenated alkyl and C 1-4 Alkyl; and R4 and R5 are each independently H or F.

2. The compound of claim 1, or its enantiomers, mixtures of enantiomers, or pharmaceutically acceptable salts thereof, wherein Q is CH.

3. The compound of claim 1, or its enantiomers, mixtures of enantiomers, or pharmaceutically acceptable salts thereof, wherein Q is N.

4. The compound of claim 1, or its enantiomers, mixtures of enantiomers, or pharmaceutically acceptable salts thereof, wherein Z is CR5.

5. The compound of claim 4, or an enantiomer thereof, a mixture of enantiomers thereof, or a pharmaceutically acceptable salt thereof, wherein R5 is H.

6. The compound of claim 4, or an enantiomer thereof, a mixture of enantiomers thereof, or a pharmaceutically acceptable salt thereof, wherein R5 is F.

7. The compound of claim 1, or its enantiomers, mixtures of enantiomers, or pharmaceutically acceptable salts thereof, wherein Z is N.

8. The compound of claim 1, or its enantiomers, mixtures of enantiomers, or pharmaceutically acceptable salts thereof, wherein R4 is H.

9. The compound of claim 1, or an enantiomer thereof, a mixture of enantiomers thereof, or a pharmaceutically acceptable salt thereof, wherein R4 is F.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has structure (IA): (IA).

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the structure (IB): (IB).

12. The compound of claim 1, or an enantiomer thereof, a mixture of enantiomers thereof, or a pharmaceutically acceptable salt thereof, wherein each of R2 is independently selected from the group consisting of: H, chlorine, fluorine, CN, methyl, ethyl, isopropyl, methoxy, trifluoromethyl, 2-fluoroethyl, difluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, cyclopropylmethyl, cyclopropyl, cyclobutyl and oxetane.

13. The compound of claim 1, or an enantiomer thereof, a mixture of enantiomers thereof, or a pharmaceutically acceptable salt thereof, wherein each of R3 is independently selected from the group consisting of: H, fluorine, chlorine, bromine, CN, methoxy, difluoromethyl, trifluoromethyl, methyl, and ethyl.

14. The compound of claim 1, wherein it is a compound having any of the following formulas: Or its enantiomers, mixtures of enantiomers, or pharmaceutically acceptable salts thereof.

15. A compound or a pharmaceutically acceptable salt thereof, said compound being:

16. A compound or a pharmaceutically acceptable salt thereof, said compound being 。 17. A compound or a pharmaceutically acceptable salt thereof, said compound being 。 18. A compound, wherein the compound is 。 19. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt as described in any one of claims 1-18; and a pharmaceutically acceptable carrier or excipient.

20. Use of the compound or pharmaceutically acceptable salt of any one of claims 1-18 or the pharmaceutical composition of claim 19 in the preparation of a medicament for treating a subject with cancer, wherein the cancer is lung cancer, glioblastoma, inflammatory myofibroblastoma (IMT), cholangiocarcinoma, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, melanoma, epithelioid angioendothelioma, esophageal cancer, renal cancer, breast cancer, colon cancer, thyroid cancer, Spitz nevus-like tumor, cholangiocarcinoma, neuroblastoma, anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), or large B-cell lymphoma.

21. The use as described in claim 20, wherein the subject is a human being.

22. The use as described in claim 20, wherein the cancer is lung cancer, glioblastoma, inflammatory myofibroblastoma (IMT), cholangiocarcinoma, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, melanoma, epithelioid angioendothelioma, esophageal cancer, renal cancer, breast cancer, colon cancer, thyroid cancer, Spitz nevus-like tumor, cholangiocarcinoma, or neuroblastoma.

23. The use as described in claim 20, wherein the cancer is anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), or large B-cell lymphoma.

24. The use as described in claim 20, wherein the cancer is lung cancer.

25. The use as described in claim 20, wherein the cancer is non-small cell lung cancer.

26. The use as claimed in claim 20, wherein the cancer is inflammatory myofibroblastoma.

27. The use as described in claim 20, wherein the cancer is ovarian cancer.

28. The use as claimed in claim 20, wherein the cancer is serous ovarian cancer.

29. The use as claimed in claim 20, wherein the cancer is Spitz nevus-like melanoma.

30. The use as claimed in claim 20, wherein the cancer is glioblastoma.

31. The use as described in claim 20, wherein the cancer is cholangiocarcinoma.

32. The use as described in claim 20, wherein the cancer is gastric cancer.

33. The use as claimed in claim 20, wherein the cancer is colorectal cancer.

34. The use as claimed in claim 20, wherein the cancer is angiosarcoma.

35. The use as described in claim 20, wherein the cancer is anaplastic large cell lymphoma.

36. The use as claimed in claim 20, wherein the cancer is diffuse large B-cell lymphoma.

37. The use as claimed in claim 20, wherein the cancer is esophageal squamous cell carcinoma.

38. The use as claimed in claim 20, wherein the cancer is renal medullary carcinoma.

39. The use as described in claim 20, wherein the cancer is renal cell carcinoma.

40. The use as described in claim 20, wherein the cancer is breast cancer.

41. The use as claimed in claim 20, wherein the cancer is papillary thyroid carcinoma.

42. The use as claimed in claim 20, wherein the cancer is neuroblastoma.

43. The use according to any one of claims 20-42, wherein the cancer is a ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) positive cancer.

44. The use according to any one of claims 20-42, wherein the cancer is an anaplastic lymphoma kinase (ALK) positive cancer.

45. The use according to any one of claims 20-42, wherein the cancer comprises the expression of an oncogenic ROS1 gene or an oncogenic ROS1 gene fusion.

46. ​​The use as claimed in claim 45, wherein the oncogenic ROS1 gene or oncogenic ROS1 gene fusion contains one or more mutations of the human ROS1 gene.

47. The use as claimed in claim 46, wherein the one or more mutations in the oncogenic ROS1 gene or oncogenic ROS1 gene fusion result in the expression of the ROS1 protein having the G2032R mutation.

48. The use according to any one of claims 20-42, wherein the cancer comprises the expression of the oncogene ALK gene or an oncogene ALK gene fusion.

49. The use as claimed in claim 48, wherein the oncogenic ALK gene or oncogenic ALK gene fusion contains one or more mutations of the human ALK gene.

50. The use as claimed in claim 49, wherein the one or more mutations in the oncogenic ALK gene or oncogenic ALK gene fusion result in the expression of an ALK protein having one or more mutations selected from the group consisting of G1202R, G1202del, L1196M, L1196Q, L1198F, G1269A, D1203N, I1171N, I1171S, I1171T, F1174L, F1174C, F1174L, V1180L, C1156Y, S1206Y, E1210K, and R1275Q, or wherein the one or more mutations in the oncogenic ALK gene or oncogenic ALK gene fusion result in the expression of a co-mutated ALK protein having G1202R and one or more mutations selected from L1196M, G1269A, and L1198F.

51. The use as described in any one of claims 20-42, wherein the cancer is metastatic, recurrent, or refractory.

52. The use as claimed in claim 51, wherein the cancer includes brain metastases.

53. The use as claimed in any one of claims 20 to 42, wherein the medicament is prepared for administration in combination with one or more additional therapeutic agents.

54. The use as described in claim 53, wherein the one or more additional therapeutic agents are TKIs.

55. The use as described in claim 54, wherein the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, loprotinib, cabozantinib, furitinib, taletinib, mesatinib, masatinib, or ensartinib.

56. The use as described in claim 53, wherein the one or more additional therapeutic agents are selected from chemotherapeutic agents, immuno-oncology agents, SH2 inhibitors, MEK inhibitors, MET inhibitors, SHP2 inhibitors, anti-PD1 agents, and RAS inhibitors.

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